Process for producing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, and salt thereof

ABSTRACT

There are disclosed are  
     A diastereomer salt of formula (1):  
                 
 
     a process for producing the same,  
     a process for producing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid of formula (2′):  
                 
 
     a novel optically active amine compound of formula (4):  
                 
 
     a novel optically active amine compound of formula (8):  
                 
 
     an imine compound of formula (7) or (11):

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to a method for producing opticallyactive 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid by resolvingracemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with anoptically active amine compound, novel optically active amine compoundtherefor and its production process.

[0003] 2. Description of Related Art

[0004] Optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acidis a useful intermediate compound of pharmaceuticals for urinaryincontinence as described in WO97/14672 and also of agrochemicals.

[0005] There have been reported a method in which racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid is resolved withoptically active α-methylbenzylamine (J. Med. Chem, 1996, 39, 4592-4601)and a method in which racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid is optically resolvedwith brucine and followed by repeated recrystallization (J. Chem. Soc.,1951, 2329-2332).

SUMMARY OF THE INVENTION

[0006] An object of the present invention is to provide a diastereomersalt comprising a specific optically active amine and optically active3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, which is suitable forproducing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionicacid having good optical purity,

[0007] another object of the invention is to provide a process forproducing optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionicacid in industrially advantageous manner,

[0008] further objects of the invention are to provide

[0009] novel optically active amine compounds suitable for opticalresolution,

[0010] intermediate compounds for producing the optically active amines,and

[0011] processes for producing the intermediate compounds.

[0012] The present invention provides:

[0013] 1. A diastereomer salt of formula (1):

[0014] wherein each asymmetric carbon atom denoted by the symbol * isindependently in S configuration or R configuration,

[0015] R₁ represents a lower alkyl group which may be substituted with ahydroxy group, or

[0016] an optionally substituted aryl group,

[0017] R₂ represents a lower alkyl group which may be substituted with ahydroxy group, or an optionally substituted aralkyl group, and

[0018] R₃ represents a lower alkyl group which may be substituted with ahydroxy group, a hydrogen atom, a cyclohexyl group, or an optionallysubstituted aralkyl group,

[0019] provided that R₁ and R₂ are not the same, and when R₁ is a phenylgroup and R₂ is a methyl group, R₅ is not a hydrogen atom;

[0020] 2. A method for producing a diastereomer salt of formula (1) asdefined above, which comprises contacting racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid of formula (2):

[0021] with an optically active amine of formula (3):

[0022] wherein the symbol *, R₁, R₂, and R₃ respectively represent thesame as defined above to form diastereomer salt(s), and separating saiddiastereomer salt of formula (1);

[0023] 3. A method for producing an optically active3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid of formula (2′):

[0024] wherein an asymmetric carbon atom denoted by the symbol * is in Sconfiguration or R configuration,

[0025] which comprises treating the salt of formula (1) as definedabove, with an acid, or a base and an acid;

[0026] 4. An optically active amine compound of formula (4):

[0027] wherein an asymmetric carbon atom denoted by the symbol * is in Sconfiguration or R configuration,

[0028] R₁₁ represents an aryl group which may be substituted with atleast one group selected from a C1-C4 alkyl group, a C1-C4 alkoxy group,a nitro group and a halogen atom,

[0029] R₂₁ represents a C1-C4 alkyl group, or an aralkyl group which maybe substituted, and

[0030] R₃₁ is a 3-benzyloxyphenyl group or a 4-benzyloxyphenyl group, ora salt thereof;

[0031] 5. A method for producing an optically active amine compound offormula (4) as defined above, or a salt thereof, which comprises:

[0032] reducing an imine compound of formula (7);

[0033] wherein the symbol *, R₁₁, R₂₁ and R₃₁ respectively have the samemeaning as defined above, to a reduction reaction;

[0034] 6. An imine compound of formula (7) as defined above,

[0035] 7. A method for producing an imine compound of formula (7) asdefined above, which comprises:

[0036] reacting an optically active amine of formula (5):

[0037] wherein the symbol * denotes an asymmetric carbon atom,

[0038] R₁₁ and R₂₁ respectively represent the same as defined above,with a benzyloxybenzaldehyde of formula (6):

R₃₁—CHO   (6)

[0039] wherein R₃₁ represents a 3-benzyloxyphenyl group or a4-benzyloxyphenyl group;

[0040] 8. An optically active amine compound of formula (8):

[0041] wherein X₁ represents a halogen atom, or a lower alkyl group,

[0042] X₂ to X₅ are the same or different and independently represent ahydrogen atom, a halogen atom, a nitro group or a lower alkyl group,

[0043] R₂₂ represents a lower alkyl group, and

[0044] R₃₂ represents an aryl group substituted with at least one groupselected from a lower alkyl group, a lower alkoxy group, an aryl group,and an aryloxy group;

[0045] 9. A method for producing an optically active amine compound offormula (8) as defined above, which comprises:

[0046] subjecting an imine compound of formula (11):

[0047] wherein X₁ to X₅, R₂₂ and R₃₂ are the same as defined above, to areduction reaction.

[0048] 10. An imine compound of formula (11) as defined above; and

[0049] 11. A method for producing an imine compound of formula (11) asdefined above, which comprises:

[0050] reacting an optically active amine compound of formula (9):

[0051] wherein X₁ to X₅ and R₂₂ are the same as defined above, with analdehyde of formula (10):

R₃₂—CHO   (10)

[0052] wherein R₃₂ represents the same as defined above.

DETAILED DESCRIPTION OF THE INVENTION

[0053] First a description will be made to the diastereomer salt offormula (1).

[0054] Racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2) canbe prepared by a known method as disclosed in J. Chem. Soc., 1951,2329-2332 or the like.

[0055] The substituent groups R₁, R₂, and R₃ of the optically activeamine compound of formula (3) will be explained below.

[0056] Examples of the lower alkyl group which may be substituted with ahydroxy group, in R₁, R₂, and R₃ include a C1-C4 alkyl group which maybe substituted with a hydroxy group.

[0057] Specific examples thereof include a methyl group, an ethyl group,a n-propyl group, an isopropyl group, a t-butyl group, a sec-butylgroup, an i-butyl group, a hydroxymethyl group, a 2-hydroxyethyl group,a 2-hydroxypropyl group, a 2-hydroxy-2-methylpropyl group and the like.

[0058] In R₃, the hydroxy group which may be present on the all moietyof the alkyl group which may be substituted with a hydroxy group is noton a carbon atom which is bound with the nitrogen atom.

[0059] Examples of the optionally substituted aryl group, in R₁ includea phenyl group, a naphthyl group and the like, all of which may besubstituted with at least one group selected from a C1-C4 alkyl group, aC1-C4 alkoxy group, a nitro group and a halogen atom.

[0060] The C1-C4 alkyl group on the aromatic ring of the aryl groupsincludes a methyl group, an ethyl group, a n-propyl group, an isopropylgroup, a t-butyl group, a sec-butyl group and an i-butyl group.

[0061] The C1-C4 alkoxy group on the aromatic ring of the aryl groupsincludes a methoxy group, an ethoxy group, a n-propoxy group, anisopropoxy group, a t-butoxy group and the like.

[0062] Examples of the halogen atom on the aromatic ring include afluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0063] Specific examples of the optionally substituted aryl groupinclude a phenyl group, a naphthyl group, a 4-methylphenzyl group, a4-ethylphenyl group, a 4-propylphenyl group, a 4-isopropylphenyl group,a 4-t-butylphenyl group, a 2,5-dimethylphenyl group, a2,4,6-trimethylphenyl group, a 2-fluorophenyl group, a 3-fluorophenylgroup, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenylgroup, a 4-chlorophenyl group, a 2,4-dichlorophenyl group, a2,3-dichlorophenyl group, a 4-bromophenyl group, a 2-methoxyphenylgroup, a 4-methoxyphenyl group, a 2-ethoxyphenyl group, a2-propoxyphenyl group, a 3,4-dimethoxyphenyl group, a2-methoxy-5-fluorophenyl group and the like.

[0064] The optionally substituted aralklyl group, in R₂ and R₃ include aC7-C12 aralkyl group

[0065] of which aryl group may be substituted with at least one groupselected from a C1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group,a halogen atom, a C6-C10 aryl group, a C6-C10 aryloxy group, a C7-C12aralkyl group and a C7-C12 aralkyloxy group, the last four of which maybe substituted on each aromatic ring with at least one group selectedfrom a C1-C4 alkyl group, a C1-C4 alkoxy group and a halogen atom, and

[0066] of which alkyl group (e.g., a methyl or ethyl group) may besubstituted with a hydroxy group.

[0067] The aryl groups in the above-described aryl, aryloxy, aralkyl andaralkyloxy groups include a C6-C10 aryl group such as a phenyl ornaphthyl group.

[0068] The alkyl moiety, in the aralkyl group, which may be substitutedwith a hydroxyl group include a methyl group or ethyl group, ahydroxymethyl group or hydroxyethyl group.

[0069] The C1-C4 alkyl group, the C1-C4 alkoxy group and the halogenatom, all of which may be present on the aryl group include the samegroups as specified above.

[0070] Specific examples of the aryloxy group include a phenoxy,1-naphthoxy and 2-naphthoxy group and the like.

[0071] Specific examples of the aralkyl groups include a benzyl group, aphenylethyl group, 1-naphtylmethyl group, 2-naphtylmethyl group and thelike.

[0072] Specific examples of the aralkyloxy group include a benzyloxygroup, 1-naphtylmethoxy group, 2-naphtylmethoxy group and the like.

[0073] Specific examples of the optionally substituted aralkyl group, inR₂ and R₃ include a benzyl group, a naphthylmethyl group, a3-methylbenzyl group, a 4-methylbenzyl group, a 4-ethylbenzyl group, a4-propylbenzyl group, a 4-isopropylbenzyl group, a 4-t-butylbenzylgroup, a 2,5-dimethylbenzyl group, a 2,4,6-trimethylbenzyl group, a2-fluorobenzyl group, a 3-fluorobenzyl group, a 4-fluorobenzyl group, a2-chlorobenzyl group, a 3-chlorobenzyl group, a 4-chlorobenzyl group, a2,4-dichlorobenzyl group, a 2,3-dichlorobenzyl group, a 4-bromobenzylgroup, a 2-methoxybenzyl group, a 3-methoxybenzyl group, a4-methoxybenzyl group, a 2-ethoxybenzyl group, a 2-propoxybenzyl group,a 3,4-dimethoxybenzyl group, a 2-methoxy-5-fluorobenzyl group, a2-phenylethyl group, an α-hydroxybenzyl group, anα-hydroxy-4-methylbenzyl group, an α-hydroxy-4-methoxybenzyl group, anα-hydroxy-4-nitrobenzyl group, an α-hydroxy-4-chlorobenzyl group, a3-phenoxybenzyl group, a 4-phenoxybenzyl group, a 3-phenylbenzyl group,a 4-phenylbenzyl group, a 3-benzyloxybenzyl group, a 4-benzyloxybenzylgroup and the like.

[0074] Specific examples of the optically active amine (3) includeoptically active isomers of α-ethylbenzylamine, α-propylbenzylamine,α-isopropybenzylamine, α, 4-dimethylbenzylamine,α,2,5-trimethylbenzylamine, α,2,4,6-tetramethylbenzylamine,α-methyl-4-isopropylbenzylamine, 2-fluoro-α-methylbenzylamine,3-fluoro-α-methylbenzylamine, 4-fluoro-α-methylbenzylamine,4-bromo-α-methylbenzylamine, 2-chloro-α-methylbenzylamine,3-chloro-α-methylbenzylamine, 4-chloro-α-methylbenzylamine,2,3-dichloro-α-methylbenzylamine, 2,4-dichloro-α-methylbenzylamine,2-methoxy-α-methylbenzylamine, 4-methoxy-α-methylbenzylamine,2-ethoxy-α-methylbenzylamine, 3,4-dimethoxy-α-methylbenzylamine,5-fluoro-2-methoxy-α-methylbenzylamine, α,β-diphenylethylamine,1-phenyl-2-(p-tolyl)ethylamine, α-phenyl-β-(3-methoxyphenyl)ethylamine,α-phenyl-β-(4-chlorophenyl)ethylamine, α,γ-diphenylpropylamine,α-methyl-1-naphthylamine, α-methyl-2-naphthylmethylamine,N-benzyl-α-methylbenzylamine, N-(2-naphthylmethyl)-α-methylbenzylamine,N-(3-benzyloxybenzyl)-α-methylbenzylamine,N-(4-phenylbenzyl)-α-methylbenzylamine,N-(3-benzyloxybenzyl)-1-phenyl-2-(p-tolyl)ethylamine,N-(4-phenylbenzyl)-1-phenyl-2-(p-tolyl)ethylamine,N-benzyl-2,4-dichloro-α-methylbenzylamine,N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine,N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine,N-(3-chlorobenzyl)-α-methylbenzylamine,N-(4-chlorobenzyl)-α-methylbenzylamine,N-(3-nitorobenzyl)-α-methylbenzylamine,N-(4-nitrobenzyl)-α-methylbenzylamine, norephedrine,2-amino-1-phenyl-1-butanol, 2-amino-3-methyl-1-phenyl-1-butanol,2-amino-1-(4-methylphenyl)-1-propanol,2-amino-1-(4-nitrophenyl)-1-propanol,2-amino-1-(4-chlorophenyl)-1-propanol, 2-amino-1,2-diphenylethanol,2-amino-1-phenyl-2-(p-tolyl)ethanol,2-amino-1-phenyl-2-(4-chlorophenyl)ethanol,2-amino-1-phenyl-2-(4-methoxyphenyl)ethanol,N-benzyl-2-amino-1-phenyl-1-propanol,N-benzyl-2-amino-1-phenyl-1-butanol,N-benzyl-2-amino-3-methyl-1-phenyl-1-butanol,N-benzyl-2-amino-1-(4-methylphenyl)-1-propanol,N-benzyl-2-amino-1-(4-nitrophenyl)-1-propanol,N-benzyl-2-amino-1-(4-chlorophenyl)-1-propanol,N-benzyl-2-amino-1,2-diphenylethanol,N-benzyl-2-amino-1-phenyl-2-(p-tolyl)ethanol,N-benzyl-2-amino-1-phenyl-2-(4-chlorophenyl)ethanol,N-benzyl-2-amino-1-phenyl-2-(4-methoxyphenyl)ethanol,N-(3-benzyloxybenzyl)-2-amino-1-phenyl-1-propanol,N-(4-phenylbenzyl)-2-amino-1-phenyl-1-propanol,N-(2-naphthylmethyl)-2-amino-1-phenyl-1-propanol,N-(4-methylbenzyl)-2-amino-1-phenyl-1-propanol,N-(3-chlorobenzyl)-2-amino-1-phenyl-1-propanol,N-(4-nitorobenzyl)-2-amino-1-phenyl-1-propanol,N-(4-methoxybenzyl)-2-amino-1-phenyl-1-propanol,N-(2,5-dimethoxybenzyl)-2-amino-1-phenyl-1-propanol,N-(3-methoxybenzyl)-2-amino-1-phenyl-1-propanol, and the like.

[0075] Among these optically active amines (3), preferred are opticalisomers of α-4-dimethylbenzylamine, N-benzyl-α-methylbenzylamine,N-(3-benzyloxybenzyl)-α-methylbenzylamine,N-(4-phenylbenzyl)-α-methylbenzylamine,N-(2-naphthylmethyl)-α-methylbenzylamine,N-(3-chlorobenzyl)-α-methylbenzylamine, 1-phenyl-2-(p-tolyl)ethylamine,N-benzyl-1-phenyl-2-(p-tolyl)ethylamine,N-benzyl-2,4-dichloro-α-methylbenzylamine,N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine,N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine, norephedrine andthe like.

[0076] More preferred are

[0077] an optically active amine compound of formula (3), wherein R₁ isa phenyl group, R₂ is a 4-methylbenzyl group and R₃ is a benzyl group,

[0078] an optically active amine compound of formula (3), wherein R₁ isa methyl group, R₂ is an α-hydroxybenzyl group and R₅ is a hydrogenatom,

[0079] an optically active amine compound of formula (3), wherein R₁ isa 2,4-dichlorophenyl group, R₂ is a methyl group and R₃ is a3-benzyloxybenzyl group,

[0080] an optically active amine compound of formula (3), wherein R₁ isa 2,4-dichlorophenyl group, R₂ is a methyl group and R₃ is a4-phenylbenzyl group, which are

[0081] N-benzyl-1-phenyl-2-(p-tolyl)ethylamine,

[0082] N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine,

[0083] N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine, and

[0084] norephedrine.

[0085] The diastereomer salt of formula (1) as defined above can beproduced by a process which comprises contacting racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid of formula (2) with anoptically active amine of formula (3), typically in a solvent, to obtaindiastereomer salt(s), and isolating the desired diastereomer salt offormula (1).

[0086] The amount of the optically active amine (3) to be used isusually approximately from 0.2 to 3 moles, preferably approximately from0.4 to 1.5 moles per mol of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2).

[0087] The diastereomer salt of formula (1) formed in the resultingreaction mixture is usually precipitated, wherein the reaction mixtureis usually in solution form and optionally a solvent may be used fordissolving said reaction mixture.

[0088] Precipitation of the desired salt may be accomplished onstanding, stirring, inoculating of seed crystals, cooling and forconcentrating said solution, and precipitated salts are usuallyisolated, for example, by filtration or the like, and optionallyfollowed by washing and/or drying.

[0089] Contacting the 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid(2) with the optically active amine (3), standing, stirring, cooling,and /or concentrating of the solution of the diastereomer salts areusually conducted within a temperature range of from a melting point ofthe solution to the boiling point of the solvent, if employed, ortypically between from −20 to 60° C.

[0090] Examples of the solvent to be used include alcohols such asmethanol, ethanol, isopropyl alcohol or the like, ketones such asacetone, methyl ethyl ketone, methyl isobutyl ketone or the like, etherssuch as diethyl ether, t-butyl methyl ether, n-butyl ether,tetrahydrofuran or the like, esters such as ethyl acetate, aliphatichydrocarbons such as n-hexane, n-heptane, cyclohexane or the like,aromatic hydrocarbons such as benzene, toluene, xylene or the like,halogenated hydrocarbons such as chloroform, dichloromethane,dichloroethane, chlorobenzene or the like, aprotic polar solvents suchas dimethylformamide, acetonitrile or the like, and water, etc. Thesolvent may be used alone or as a mixture thereof.

[0091] The amount of the solvent to be used may be optionally setdepending on the kind of the optically active amine (3), the kind of thesolvent and the like, but is usually within the range of from 1 to 50parts by weight per 1 part by weight of3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2).

[0092] Examples of the diastereomer salt of formula (1) include saltscomprising optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionicacid (2′) having either S or R configuration with respect to theasymmetric carbon atom designated by * and optically active amine offormula (3) as specified above having either S or R configuration withrespect to the asymmetric carbon atom designated by *.

[0093] The optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionicacid (2′) can be obtained by a method, which comprises treating the saltof formula (1) as defined above, with an acid, or a base and an acid

[0094] Optically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid(2′) can be obtained, for example, by contacting the diastereomer salt(1) with an aqueous acid solution, or an acid and water, extracting theresulting aqueous acid layer with a hydrophobic solvent, and thenconcentrating the extract.

[0095] Alternatively, the diastereomer salt (1) may be contacted with anaqueous basic solution. After extracting the resulting aqueous basiclayer with a hydrophobic solvent, the separated aqueous layer isacidified with an acid, extracting the aqueous acid layer with ahydrophobic solvent and then concentrating the extract to yield theoptically active 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (2′).

[0096] Specific examples of the acid to be used include an inorganicacid such as hydrofluoric acid, hydrochloric acid, hydrobromic acid,sulfuric acid or the like. Among these acids, hydrochloric acid andsulfuric acid are particularly preferred.

[0097] The amount of the acid to be used is usually approximately from 1to 200 moles, preferably approximately from 2 to 20 moles per mol of thediastereomer salt (1).

[0098] Specific examples of the base to be used include alkali metalhydroxides such as lithium hydroxide, sodium hydroxide, potassiumhydroxide or the like, alkaline earth metal hydroxides such as magnesiumhydroxide, calcium hydroxide or the like, alkali carbonates such assodium carbonate, potassium carbonate or the like, alkalihydrogencarbonates such as sodium hydrogencarbonate, potassiumhydrogencarbonate or the like, etc.

[0099] The amount of the base to be used is usually approximately from 1to 200 moles, preferably approximately from 2 to 20 moles per mol of thediastereomer salt (1).

[0100] Specific examples of the hydrophobic solvent to be used forextraction in the present invention include ethers such as diethylether, t-butyl methyl ether, n-butyl ether, tetrahydrofuran or the like,esters such as ethyl acetate or the like, aliphatic hydrocarbons such asn-hexane, n-heptane, cyclohexane or the like, aromatic hydrocarbons suchas benzene, toluene, xylene or the like, halogenated hydrocarbons suchas chloroform, dichloromethane, dichloroethane, chlorobenzene or thelike. The hydrophobic solvent may be used alone or as a mixture thereof.

[0101] The amount of the hydrophobic solvent to be used for extractionvaries depending on the kind of the optically active amine (3) of thediastereomer salt, the kind of the solvent and the like, but it isusually within the range of from 1 to 200 parts by weight per 1 part byweight of the diastereomer salt (1).

[0102] The amount of water, or aqueous acidic solution to be used forthe dissolution of the diastereomeric salt (1) varies depending on thekind of the optically active amine (3) of the diastereomer salt and thelike, but it is usually within the range of from 1 to 200 parts byweight per 1 part by weight of the diastereomer salt (1).

[0103] The extraction is usually conducted at a temperature range offrom the melting point to the boiling point of water and the solvent tobe used, preferably approximately from 0 to 60° C.

[0104] According to the present invention, the optically active3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, which is useful as anintermediate for producing pharmaceuticals or agrochemicals, can beobtained in good optical purity in an industrial scale.

[0105] The optically active amine compound of formula (3) include noveloptically active amine compounds of formulae (4) and (8).

[0106] In the novel optically active compound of formula (4), the arylgroup which may be substituted with at least one group selected from aC1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group and a halogenatom, in R₁₁ include the same groups as defined for R₁ above.

[0107] The optionally substituted aralkyl group and the C1-C4 alkylgroup, in R₂₁ respectively represent the same groups as defined for R₂above.

[0108] R₃₁ represents a 3-benzyloxyphenyl group or a 4-benzyloxyphenylgroup.

[0109] Specific examples of the optically active amine compound (4) or asalt thereof include optically active isomers of

[0110] N-(3-benzyloxybenzyl)-α-methylbenzylamine,

[0111] N-(3-benzyloxybenzyl)-α-ethylbenzylamine,

[0112] N-(3-benzyloxybenzyl)-α-propylbenzylamine,

[0113] N-(3-benzyloxybenzyl)-α-isopropylbenzylamine,

[0114] N-(3-benzyloxybenzyl)-α,4-dimethylbenzylamine,

[0115] N-(3-benzyloxybenzyl)-α,2,5-trimethylbenzylamine,

[0116] N-(3-benzyloxybenzyl)-α,2,4,6-tetramethylbenzylamine,

[0117] N-(3-benzyloxybenzyl)-α-methyl-4-isopropylbenzylamine,

[0118] N-(3-benzyloxybenzyl)-2-fluoro-α-methylbenzylamine,

[0119] N-(3-benzyloxybenzyl)-3-fluoro-α-methylbenzylamine,

[0120] N-(3-benzyloxybenzyl)-4-fluoro-α-methylbenzylamine,

[0121] N-(3-benzyloxybenzyl)-4-bromo-α-methylbenzylamine,

[0122] N-(3-benzyloxybenzyl)-2-chloro-α-methylbenzylamine,

[0123] N-(3-benzyloxybenzyl)-3-chloro-α-methylbenzylamine,

[0124] N-(3-benzyloxybenzyl)-4-chloro-α- methylbenzylamine,

[0125] N-(3-benzyloxybenzyl)-2,3-dichloro-α-methylbenzylamine,

[0126] N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine,

[0127] N-(3-benzyloxybenzyl)-2-methoxy-α-methylbenzylamine,

[0128] N-(3-benzyloxybenzyl)-4-methoxy-α-methylbenzylamine,

[0129] N-(3-benzyloxybenzyl)-2-ethoxy-α-methylbenzylamine,

[0130] N-(3-benzyloxybenzyl)-3,4-dimethoxy-α-methylbenzylamine,

[0131] N-(3-benzyloxybenzyl)-5-fluoro-2-methoxy-α-methylbenzylamine,

[0132] N-(3-benzyloxybenzyl)-α,β-diphenylethylamine,

[0133] N-(3-benzyloxybenzyl)-1-phenyl-2-(p-tolyl)ethylamine,

[0134] N-(3-benzyloxybenzyl)-α-phenyl-β-(3-methoxyphenyl)ethylamine,

[0135] N-(3-benzyloxybenzyl)-α-phenyl-β-(4-chlorophenyl)ethylamine,

[0136] N-(3-benzyloxybenzyl)-α,γ-diphenylpropylamine,

[0137] N-(3-benzyloxybenzyl)-α-methyl-1-naphthylamine,

[0138] N-(3-benzyloxybenzyl)-α-methyl-2-naphthylmethylamine,

[0139] N-(4-benzyloxybenzyl)-α-methylbenzylamine,

[0140] N-(4-benzyloxybenzyl)-α-ethylbenzylamine,

[0141] N-(4-benzyloxybenzyl)-α-propylbenzylamine,

[0142] N-(4-benzyloxybenzyl)-α-isopropylbenzylamine,

[0143] N-(4-benzyloxybenzyl)-α,4-dimethylbenzylamine,

[0144] N-(4-benzyloxybenzyl)-α,2,5-trimethylbenzylamine,

[0145] N-(4-benzyloxybenzyl)-α,2,4,6-tetramethylbenzylamine,

[0146] N-(4-benzyloxybenzyl)-2-fluoro-α-methylbenzylamine,

[0147] N-(4-benzyloxybenzyl)-3-fluoro-α-methylbenzylamine,

[0148] N-(4-benzyloxybenzyl)-4-fluoro-α-methylbenzylamine,

[0149] N-(4-benzyloxybenzyl)-4-bromo-α-methylbenzylamine,

[0150] N-(4-benzyloxybenzyl)-2-chloro-α-methylbenzylamine,

[0151] N-(4-benzyloxybenzyl)-3-chloro-α-methylbenzylamine,

[0152] N-(4-benzyloxybenzyl)-4-chloro-α-methylbenzylamine,

[0153] N-(4-benzyloxybenzyl)-2,3-dichloro-α-methylbenzylamine,

[0154] N-(4-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine,

[0155] N-(4-benzyloxybenzyl)-2-methoxy-α-methylbenzylamine,

[0156] N-(4-benzyloxybenzyl)4-methoxy-α-methylbenzylamine,

[0157] N-(4-benzyloxybenzyl-2-ethoxy-α-methylbenzylamine,

[0158] N-(4-benzyloxybenzyl)-3,4-dimethoxy-α-methylbenzylamine,

[0159] N-(4-benzyloxybenzyl)-5-fluoro-2-methoxy-α-methylbenzylamine,

[0160] N-(4-benzyloxybenzyl)-α,β-diphenylethylamine,

[0161] N-(4-benzyloxybenzyl)-1-phenyl-2-p-tolyl)ethylamine,

[0162] N-(4-benzyloxybenzyl)-α-phenyl-β-(3-methoxyphenyl)ethylamine,

[0163] N-(4-benzyloxybenzyl)-α-phenyl-p-(4-chlorophenyl)ethylamine,

[0164] N-(4-benzyloxybenzyl)-α,γ-diphenylpropylamine,

[0165] N-(4-benzyloxybenzyl)-α-methyl-1-naphthylamine,

[0166] N-4-benzyloxybenzyl)-α-methyl-2-naphthylmethylamine, and saltsthereof with an inorganic acid such as hydrochloric acid, sulfuric acid,nitric acid or the like.

[0167] Preferred are

[0168] optically active amine compounds of formula (4), wherein R₁₁ is aphenyl group and R₂₁ is a methyl group, and

[0169] optically active amine compounds of formula (4), wherein R₁₁ is a2,4-dichlorophenyl group and R₂₁ is a methyl group.

[0170] The optically active amine compound (4) can be obtained, forexample, by a process, which comprises subjecting the imine compound offormula (7) to a reduction reaction.

[0171] In the imine compound of formula (7), R₁₁, R₂₁ and R₃₁ are asdefined above for the optically active amine compound of formula (4).

[0172] Specific examples of the imine compound (7) include:

[0173] N-(3-benzyloxybenzylidene)α-methylbenzylamine,

[0174] N-(3-benzyloxybenzylidene)-α-ethylbenzylamine,

[0175] N-(3-benzyloxybenzylidene)-α-propylbenzylamine,

[0176] N-(3-benzyloxybenzylidene)-α-isopropylbenylamine,

[0177] N-(3-benzyloxybenzylidene)-α,4-dimethylbenzylamine,

[0178] N-(3-benzyloxybenzylidene)-α,2,5-trimethylbenzylamine,

[0179] N-(3-benzyloxybenzylidene)-α,2,4,6-tetramethylbenzylamine,

[0180] N-(3-benzyloxybenzylidene)-α-methyl-4-isopropylbenzylamine,

[0181] N-(3-benzyloxybenzylidene)-2-fluoro-α-methylbenzylamine,

[0182] N-(3-benzyloxybenzylidene)-3-fluoro-α-methylbenzylamine,

[0183] N-(3-benzyloxybenzylidene)-4-fluoro-α-methylbenzylamine,

[0184] N-(3-benzyloxybenzylidene)-4-bromo-α-methylbenzylamine,

[0185] N-(3-benzyloxybenzylidene)-2-chloro-α-methylbenzylamine,

[0186] N-(3-benzyloxybenzylidene)-3-chloro-α-methylbenzylamine,

[0187] N-(3-benzyloxybenzylidene)-4-chloro-α-methylbenzylamine,

[0188] N-(3-benzyloxybenzylidene)-2,3-dichloro-α-methylbenzylamine,

[0189] N-(3-benzyloxybenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0190] N-(3-benzyloxybenzylidene)-2-methoxy-α-methylbenzylamine,

[0191] N-(3-benzyloxybenzylidene)-4-methoxy-α-methylbenzylamine,

[0192] N-(3-benzyloxybenzylidene)-2-ethoxy-α-methylbenzylamine,

[0193] N-(3-benzyloxybenzylidene)-3,4-dimethoxy-α-methylbenzylamine,

[0194]N-(3-benzyloxybenzylidene)-5-fluoro-2-methoxy-α-methylbenzylamine,

[0195] N-(3-benzyloxybenzylidene)-α,β-diphenylethylamine,

[0196] N-(3-benzyloxybenzylidene)-1-phenyl-2-(p-tolyl)ethylamine,

[0197]N-(3-benzyloxybenzylidene)-α-phenyl-β-(3-methoxyphenyl)ethylamine,

[0198] N-(3-benzyloxybenzylidene)-α-phenyl-β-(4-chlorophenyl)ethylamine,

[0199] N-(3-benzyloxybenzylidene)-α,γ-diphenylpropylamine,

[0200] N-(3-benzyloxybenzylidene)-α-methyl-1-naphthylamine,

[0201] N-(3-benzyloxybenzylidene)-α-methyl-2-naphthylmethylamine,

[0202] N-(4-benzyloxybenzylidene)-α-methylbenzylamine,

[0203] N-(4-benzyloxybenzylidene)-α-ethylbenzylamine,

[0204] N-(4-benzyloxybenzylidene)-α-propylbenzylamine,

[0205] N-(4-benzyloxybenzylidene)-α-isopropylbenzylamine,

[0206] N-(4-benzyloxybenzylidene)-α,4-dimethylbenzylamine,

[0207] N-(4-benzyloxybenzylidene)-α,2,5-trimethylbenzylamine,

[0208] N-(4-benzyloxybenzylidene)-α,2,4,6-tetramethylbenzylamine,

[0209] N-(4-benzyloxybenzylidene)-α-methyl-4-isopropylbenzylamine,

[0210] N-(4-benzyloxybenzylidene)-2-fluoro-α-methylbenzylamine,

[0211] N-(4-benzyloxybenzylidene)-3-fluoro-α-methylbenzylamine,

[0212] N-(4-benzyloxybenzylidene)-4-fluoro-α-methylbenzylamine,

[0213] N-(4-benzyloxybenzylidene)-4-bromo-α-methylbenzylamine,

[0214] N-(4-benzyloxybenzylidene)-2-chloro-α-methylbenzylamine,

[0215] N-(4-benzyloxybenzylidene)-3-chloro-α-methylbenzylamine,

[0216] N-(4-benzyloxybenzylidene)-4-chloro-α-methylbenzylamine,

[0217] N-(4-benzyloxybenzylidene)-2,3-dichloro-α-methylbenzylamine,

[0218] N-(4-benzyloxybenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0219] N-(4-benzyloxybenzylidene)-2-methoxy-α-methylbenzylamine,

[0220] N-(4-benzyloxybenzylidene)-4-methoxy-α-methylbenzylamine,

[0221] N-(4-benzyloxybenzylidene)-2-ethoxy-α-methylbenzylamine,

[0222] N-(4-benzyloxybenzylidene)-3,4-dimethoxy-α-methylbenzylamine,

[0223]N-(4-benzyloxybenzylidene)-5-fluoro-2-methoxy-α-methylbenzylamine,

[0224] N-(4-benzyloxybenzylidene)-α,β-diphenylethylamine,

[0225] N-(4-benzyloxybenzylidene)-1-phenyl-2-(p-tolyl)ethylamine,

[0226]N-(4-benzyloxybenzylidene)-α-phenyl-β-(3-methoxyphenyl)ethylamine,

[0227] N-(4-benzyloxybenzylidene)-α-phenyl-β-(4-chlorophenyl)ethylamine,

[0228] N-(4-benzyloxybenzylidene)-α,γ-diphenylpropylamine,

[0229] N-(4-benzyloxybenzylidene)-α-methyl-1-naphthylamine,

[0230] N-(4-benzyloxybenzylidene)-α-methyl-2-naphthylmethylamine and thelike.

[0231] The reduction reaction is usually conducted, for example, by aprocess which comprises reacting the imine compound of formula (7) witha reducing agent such as a metal hydride or the like, alternatively withhydrogen in the presence of a catalyst.

[0232] Examples of the metal hydride include lithium aluminum hydride,sodium borohydride and borane and the like. Borane includes diborane,borane-THF, a borane-sulfide complex, a borane-amine complex and thelike.

[0233] The amount of the reducing agent to be used is usually within therange of approximately from 0.25 to 5 moles, preferably approximatelyfrom 0.25 to 2 moles per mol of the imine compound (7) in the case wherelithium aluminum hydride or sodium borohydride is used.

[0234] When borane is used, the amount of borane to be used, on a boronebasis, is usually within the range of approximately from 0.3 to 5 moles,preferably approximately from 0.3 to 3 moles per mol of the iminecompound (7).

[0235] The reduction reaction is usually conducted in an inert solvent.Examples of the inert solvents include ethers such as diethyl ether,t-butyl methyl ether, n-butyl ether, tetrahydrofuran or the like,aromatic hydrocarbons such as benzene, toluene, xylene or the like,halogenated hydrocarbons such as chloroform, dichloromethane,dichloroethane, chlorobenzene or the like.

[0236] When sodium borohydride is used as a reducing agent, a loweralcohol such as methanol, ethanol, isopropyl alcohol or the like as wellas the aforementioned solvents. The solvent may be used alone or as amixture thereof The amount of the solvent to be used is not particularlylimited.

[0237] The reaction is usually conducted within a temperature range ofapproximately of from −50° C. to 100° C., preferably from −20° C. to100° C.

[0238] After completion of the reaction, the optically active aminecompound (4) is usually obtained, for example, by treating the resultingreaction mixture with water, acetic acid or an inorganic acid, and thenextracted with a hydrophobic organic solvent under alkaline conditions,which was made by adding an appropriate amount of a base, phaseseparation of the organic phase and concentration thereof under aneutral or weakly basic condition. The product may be further purifiedby recrystallization, and/or column chromatography using silica gel,etc., if necessary.

[0239] Examples of the catalyst to be used for hydrogenation includeRaney nickel, palladium-carbon, platinum dioxide, platinum black and thelike.

[0240] The amount of such a catalyst to be used is usually from 0.1 to100% by weight, preferably from 0.5 to 50% by weight per 1 part byweight of the imine compound (7).

[0241] An inert solvent may be used in the hydrogenation reaction.Examples of the solvent include alcohols such as methanol, ethanol,isopropyl alcohol or the like, ethers such as diethyl ether, t-butylmethyl ether, n-butyl ether, tetrahydrofuran or the like, esters such asethyl acetate, aromatic hydrocarbons such as benzene, toluene, xylene orthe like, water, etc. These solvents may be used alone or as a mixturethereof. The amount of the solvent to be used is not particularlylimited.

[0242] The hydrogenation is usually conducted within the range ofapproximately from −30° C. to 150° C., preferably from −10° C. to 100°C.

[0243] The hydrogenation is usually conducted at a pressure ofapproximately from 0 to 10 MPa (0 to 100 kg/cm²), preferablyapproximately from 0 to 5 MPa (0 to 50 kg/cm²).

[0244] After completion of the reaction, the optically active aminecompound (4) can be obtained, for example, by removing the catalyst byfiltration, followed by concentrating the filtrate. The desired productmay be further purified by recrystallization and/or columnchromatography using silica gel, if necessary.

[0245] The imine compound (7) is usually obtained by a process, whichcomprises reacting the optically active amine (5) with thebenzyloxybenzaldehyde (6).

[0246] In the optically active amine (5), R₁₁ and R₂₁ are as definedabove for the optically active compound of formula (4).

[0247] Examples of the optically active amine (5) include opticalisomers of α-methylbenzylamine, 1-(1-naphthyl)ethylamine,α,4-dimethylbenzylamine, 4-isopropyl-α-methylbenzylamine,4-nitro-α-methylbenzylamine, 4-bromo-α-methylbenzylamine,α-ethylbenzylamine, α-isopropylbenzylamine,1-phenyl-2-(p-tolyl)ethylamine and the like. These amines arecommercially available or can be readily obtained by a known method.Alternatively, the optically active amine (5) can be obtained by asimilar manner as disclosed in a reference such as Houben-Weyl, Methodender Organischen Chemie, Georg-Thieme-Verlag,, Stuttgart and the like.

[0248] Examples of the benzyloxybenzaldehyde of formula (6): R₃₁—CHOinclude 3-benzyloxybenzaldehyde and 4-benzyloxybenzaldehyde. Thesealdehydes are commercially available.

[0249] The optically active amine (5) is usually reacted with thebenzyloxybenzaldehyde of formula (6) in a solvent. Examples of thesolvent include alcohols such as methanol, ethanol, isopropyl alcohol orthe like, ethers such as diethyl ether, t-butyl methyl ether, n-butylether, tetrahydrofuran or the like, aromatic hydrocarbons such asbenzene, toluene, xylene or the like, halogenated hydrocarbons such aschloroform, dichloromethane, dichloroethane, chlorobenzene or the like.

[0250] The solvent may be used alone or as a mixture thereof.

[0251] The amount of the benzyloxybenzaldehyde (6) is usually 1 to 1.2moles per mole of the optically active amine (5).

[0252] The reaction temperature is usually within the range of from 0°C. to 200° C., preferably from 0° C. to 150° C.

[0253] Although the obtained imine compound (7) can be isolated byevaporation and the like, it may be used in the subsequent reaction asit is without being isolated.

[0254] Next descriptions will be made to the optically active aminecompound of formula (8) as defined above, a process for producing thesame, the imine compound (11) and processes of using and producing thesame.

[0255] In the novel optically active compound of formula (8), thehalogen atom represented by X₁ to X₅ have the same meanings as definedabove.

[0256] The lower alkyl group represented by R₂₂ or X₂ to X₅ include aC1-C4 alkyl group as specified for R₂ above.

[0257] Preferably, X₁ and X₃ represent halogen atoms such as chlorineand X₂, X₄ and X₅ represent hydrogen atoms.

[0258] The lower alkyl group and the lower alkoxy group on the arylgroup in R₃₂ include C1-C4 alkyl group and C1-C4 alkoxy grouprespectively.

[0259] Examples of the aryl group include C6-C10 aryl group such as aphenyl or naphthyl group.

[0260] Examples of the C6-C10 aryl group substituted with at least onegroup selected from a C1-C4 alkyl group, a C1-C4 alkoxy group, an arylgroup (e.g. a phenyl or naphthyl group) and an aryloxy group (e.g. aphenoxy or naphthoxy group), in R₃₂ include

[0261] a 1-naphthyl group,

[0262] a 2-naphthyl group, a 4-methylphenyl group, a 4-ethylphenylgroup,

[0263] a 4-propylphenyl group, a 4-isopropylphenyl group, a4-t-butylphenyl group,

[0264] a 2,5-dimethylphenyl group, a 2,4,6-trimethylphenyl group,

[0265] a 2-methoxyphenyl group, a 4-methoxyphenyl group,

[0266] a 2-ethoxyphenyl group, a 2-propoxyphenyl group,

[0267] a 3,4-dimethoxyphenyl group, a 3-phenoxyphenyl group, and

[0268] a 4-phenylphenyl group. Among these groups, preferred are3-phenoxyphenyl group and a 4-phenylphenyl group.

[0269] Specific examples the optically active amine compound of formula(8) or salts thereof include optically active isomers of

[0270] N-(4-methylbenzyl)-2-chloro-α-methylbenzylamine,

[0271] N-(2,5-dimethylbenzyl)-2-chloro-α-methylbenzylamine,

[0272] N-(2,4,6-trimethylbenzyl)-2-chloro-α-methylbenzylamine,

[0273] N-(4-isopropylbenzyl)-2-chloro-α-methylbenzylamine,

[0274] N-(2-methoxylbenzyl)-2-chloro-α-methylbenzylamine,

[0275] N-(4-methoxylbenzyl)-2-chloro-α-methylbenzylamine,

[0276] N-(2-ethoxylbenzyl)-2-chloro-α-methylbenzylamine,

[0277] N-(3,4-dimethoxybenzyl)-2-chloro-α-methylbenzylamine,

[0278] N-(3-phenoxybenzyl)-2-chloro-α-methylbenzylamine,

[0279] N-(4-phenoxybenzyl)-2-chloro-α-methylbenzylamine,

[0280] N-(2-phenylbenzyl)-2-chloro-α-methylbenzylamine,

[0281] N-(3-phenylbenzyl)-2-chloro-α-methylbenzylamine,

[0282] N-(4-phenylbenzyl)-2-chloro-α-methylbenzylamine,

[0283] N-(4-methylbenzyl)-2,3-dichloro-α-methylbenzylamine,

[0284] N-(2,5-dimethylbenzyl)-2,3-dichloro-α-methylbenzylamine,

[0285] N-(2,4,6-trimethylbenzyl)-2,3-dichloro-α-methylbenzylamine,

[0286] N-(4-isopropylbenzyl)-2,3-dichloro-α-methylbenzylamine,

[0287] N-(2-ethoxylbenzyl)-2,3-dichloro-α-methylbenzylamine,

[0288] N-(4-methoxylbenzyl)-2,3-dichloro-α-methylbenzylamine,

[0289] N-(2-ethoxylbenzyl)-2,3-dichloro-α-methylbenzylamine,

[0290] N-(3-ethoxylbenzyl)-2,3-dichloro-α-methylbenzylamine,

[0291] N-(3-phenoxybenzyl)-2,3-dichloro-α-methylbenzylamine,

[0292] N-(4-phenoxybenzyl)-2,3-dichloro-α-methylbenzylamine,

[0293] N-(2-phenylbenzyl)-2,3-dichloro-α-methylbenzylamine,

[0294] N-(3-phenylbenzyl)-2,3-dichloro-α-methylbenzylamine,

[0295] N-(4-phenylbenzyl)-2,3-dichloro-α-methylbenzylamine,

[0296] N-(4-methylbenzyl)-2,4-dichloro-α-methylbenzylamine,

[0297] N-(2,5-dimethylbenzyl)-2,4-dichloro-α-methylbenzylamine,

[0298] N-(2,4,6-trimethylbenzyl)-2,4-dichloro-α-methylbenzylamine,

[0299] N-(4-isopropylbenzyl)-2,4-dichloro-α-methylbenzylamine,

[0300] N-(2-methoxylbenzyl)-2,4-dichloro-α-methylbenzylamine,

[0301] N-(4-methoxybenzyl)-2,4-dichloro-α-methylbenzylamine,

[0302] N-(2-ethoxylbenzyl)-2,4-dichloro-α-methylbenzylamine,

[0303] N-(3,4-dimethoxybenzyl)-2,4-dichloro α-methylbenzylamine,

[0304] N-(3-phenoxybenzyl)-2,4-dichloro-α-methylbenzylamine,

[0305] N-(3,4-phenoxybenzyl)-2,4-dichloro-α-methylbenzylamine,

[0306] N-(2-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine,

[0307] N-(3-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine,

[0308] N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine,

[0309] N-(4-methylbenzyl)-2,5-dichloro-α-methylbenzylamine,

[0310] N-(2,5-dimethylbenzyl)-2,5-dichoro-α-methylbenzylamine,

[0311] N-(2,4,6-trimethylbenzyl)-2,5-dichloro-α-methylbenzylamine,

[0312] N-(4-isopropylbenzyl)-2,5-dichloro-α-methylbenzylamine,

[0313] N-(2-methoxylbenzyl)-2,5-dichloro-α-methylbenzylamine,

[0314] N-(4-methoxylbenzyl)-2,5-dichloro-α-methylbenzylamine,

[0315] N-(2-ethoxylbenzyl)-2,5-dichloro-α-methylbenzylamine,

[0316] N-(3,4-dimethoxylbenzyl)-2,5-dichloro-α-methylbenzylamine,

[0317] N-(3-phenoxybenzyl)-2,5-dichloro-α-methylbenzylamine,

[0318] N-(4-phenoxybenzyl)-2,5-dichloro-α-methylbenzylamine,

[0319] N-(2-phenylbenzyl)-2,5-dichloro-α-methylbenzylamine,

[0320] N-(3-phenylbenzyl)-2,5-dichloro-α-methylbenzylamine,

[0321] N-(4-phenylbenzyl)-2,5-dichloro-α-methylbenzylamine,

[0322] N-(4-methylbenzyl)-2,6-dichloro-α-methylbenzylamine,

[0323] N-(2,5-dimethylbenzyl)-2,6-dichloro-α-methylbenzylamine,

[0324] N-(2,4,6-trimethylbenzyl)-2,6-dichloro-α-methylbenzylamine,

[0325] N-(4-isopropylbenzyl)-2,6-dichloro-α-methylbenzylamine,

[0326] N-(2-methoxylbenzyl)-2,6-dichloro-α-methylbenzylamine,

[0327] N-(4-methoxylbenzyl)-2,6-dichloro-α-methylbenzylamine,

[0328] N-(2-ethoxylbenzyl)-2,6-dichloro-α-methylbenzylamine,

[0329] N-(3,4-dimethoxylbenzyl)-2,6-dichloro-α-methylbenzylamine,

[0330] N-(3-phenoxybenzyl)-2,6-dichloro-α-methylbenzylamine,

[0331] N-(4-phenoxybenzyl)-2,6-dichloro-α-methylbenzylamine,

[0332] N-(2-phenylbenzyl)-2,6-dichloro-α-methylbenzylamine,

[0333] N-(3-phenylbenzyl)-2,6-dichloro-α-methylbenzylamine,

[0334] N-(4-phenylbenzyl)-2,6-dichloro-α-methylbenzylamine,

[0335] N-(4-methylbenzyl)-2,4,6-trichloro-α-methylbenzylamine,

[0336] N-(2,5-dimethylbenzyl)-2,4,6-trichloro-α-methylbenzylamine,

[0337] N-(2,4,6-trimethylbenzyl)-2,4,6-trichloro-α-methylbenzylamine,

[0338] N-(4-isopropylbenzyl)-2,4,6-trichloro-α-methylbenzylamine,

[0339] N-(2-methoxylbenzyl)-2,4,6-trichloro-α-methylbenzylamine,

[0340] N-(4-methoxylbenzyl)-2,4,6-trichloro-α-methylbenzylamine,

[0341] N-(2-ethoxylbenzyl)-2,4,6-trichloro-α-methylbenzylamine,

[0342] N-(3,4-dimethoxylbenzyl)-2,4,6-trichloro-α-methylbenzylamine,

[0343] N-(3-phenoxybenzyl)-2,4,6-trichloro-α-methylbenzylamine,

[0344] N-(4-phenoxybenzyl)-2,4,6-trichloro-α-methylbenzylamine,

[0345] N-(2-phenylbenzyl)-2,4,6-trichloro-α-methylbenzylamine,

[0346] N-(3-phenylbenzyl)-2,4,6-trichloro-α-methylbenzylamine,

[0347] N-(4-phenylbenzyl)-2,4,6-trichloro-α-methylbenzylamine,

[0348] N-(4-methylbenzyl)-2,3,4-trichloro-α-methylbenzylamine,

[0349] N-(2,5-dimethylbenzyl)-2,3,4-trichloro-α-methylbenzylamine,

[0350] N-(2,4,6-trimethylbenzyl)-2,3,4-trichloro-α-methylbenzylamine,

[0351] N-(4-isopropylbenzyl)-2,3,4-trichloro-α-methylbenzylamine,

[0352] N-(2-methoxylbenzyl)-2,3,4-trichloro-α-methylbenzylamine,

[0353] N-(4-methoxylbenzyl)-2,3,4-trichloro-α-methylbenzylamine,

[0354] N-(2-ethoxylbenzyl)-2,3,4-trichloro-α-methylbenzylamine,

[0355] N-(3,4-dimethoxylbenzyl)-2,3,4-trichloro-α-methylbenzylamine,

[0356] N-(3-phenoxybenzyl)-2,3,4-trichloro-α-methylbenzylamine,

[0357] N-(4-phenoxybenzyl)-2,3,4-trichloro-α-methylbenzylamine,

[0358] N-(2-phenylbenzyl)-2,3,4-trichloro-α-methylbenzylamine,

[0359] N-(3-phenylbenzyl)-2,3,4-trichloro-α-methylbenzylamine,

[0360] N-(4-phenylbenzyl)-2,3,4-trichloro-α-methylbenzylamine,

[0361] N-(4-methylbenzyl)-2,4-difluoro-α-methylbenzylamine,

[0362] N-(2,5-dimethylbenzyl)-2,4-difluoro-α-methylbenzylamine,

[0363] N-(2,4,6-trimethylbenzyl)-2,4-difluoro-α-methylbenzylamine,

[0364] N-(4-isopropylbenzyl)-2,4-difluoro-α-methylbenzylamine,

[0365] N-(2-methoxylbenzyl)-2,4-difluoro-α-methylbenzylamine,

[0366] N-(4-methoxylbenzyl)-2,4-difluoro-α-methylbenzylamine,

[0367] N-(2-ethoxylbenzyl)-2,4-difluoro-α-methylbenzylamine,

[0368] N-(3,4-dimethoxylbenzyl)-2,4-difluoro-α-methylbenzylamine,

[0369] N-(3-phenoxybenzyl)-2,4-difluoro-α-methylbenzylamine,

[0370] N-(4-phenoxybenzyl)-2,4-difluoro-α-methylbenzylamine,

[0371] N-(2-phenylbenzyl)-2,4-difluoro-α-methylbenzylamine,

[0372] N-(3-phenylbenzyl)-2,4-difluoro-α-methylbenzylamine,

[0373] N-(4-phenylbenzyl)-2,4-difluoro-α-methylbenzylamine,

[0374] N-(4-methylbenzyl)-2,4-difluoro-α-methylbenzylamine,

[0375] N-(2,5-dimethylbenzyl)-2,4-dibromo-α-methylbenzylamine,

[0376] N-(2,4,6-trimethylbenzyl)-2,4-dibromo-α-methylbenzylamine,

[0377] N-(4-isopropylbenzyl)-2,4-dibromo-α-methylbenzylamine,

[0378] N-(2-methoxylbenzyl)-2,4-dibromo-α-methylbenzylamine,

[0379] N-(4-methoxylbenzyl)-2,4-dibromo-α-methylbenzylamine,

[0380] N-(2-ethoxylbenzyl)-2,4-dibromo-α-methylbenzylamine,

[0381] N-(3,4-dimethoxylbenzyl)-2,4-dibromo-α-methylbenzylamine,

[0382] N-(3-phenoxybenzyl)-2,4-dibromo-α-methylbenzylamine,

[0383] N-(4-phenoxybenzyl)-2,4-dibromo-α-methylbenzylamine,

[0384] N-(2-phenylbenzyl)-2,4-dibromo-α-methylbenzylamine,

[0385] N-(3-phenylbenzyl)-2,4-dibromo-α-methylbenzylamine,

[0386] N-(4-phenylbenzyl)-2,4-dibromo-α-methylbenzylamine,

[0387] N-(4-methylbenzyl)-2,4-diiodo-α-methylbenzylamine,

[0388] N-(2,5-dimethylbenzyl)-2,4-diiodo-α-methylbenzylamine,

[0389] N-(2,4,6-trimethylbenzyl)-2,4-diiodo-α-methylbenzylamine,

[0390] N-(4-isopropylbenzyl)-2,4-diiodo-α-methylbenzylamine,

[0391] N-(2-methoxylbenzyl)-2,4-diiodo-α-methylbenzylamine,

[0392] N-(4-methoxylbenzyl)-2,4-diiodo-α-methylbenzylamine,

[0393] N-(2-ethoxylbenzyl)-2,4-diiodo-α-methylbenzylamine,

[0394] N-(3,4-dimethoxylbenzyl)-2,4-diiodo-α-methylbenzylamine,

[0395] N-(3-phenoxybenzyl)-2,4-diiodo-α-methylbenzylamine,

[0396] N-(4-phenoxybenzyl)-2,4-diiodo-α-methylbenzylamine,

[0397] N-(2-phenylbenzyl)-2,4-diiodo-α-methylbenzylamine,

[0398] N-(3-phenylbenzyl)2,4-diiodo-α-methylbenzylamine,

[0399] N-(4-phenylbenzyl)-2,4-diiodo -α-methylbenzylamine,

[0400] N-(4-methylbenzyl)-2,4-dimethyl-α-methylbenzylamine,

[0401] N-(2,5-dimethylbenzyl)-2,4-dimethyl-α-methylbenzylamine,

[0402] N-(2,4,6-trimethylbenzyl)-2,4-dimethyl-α-methylbenzylamine,

[0403] N-(4-isopropylbenzyl)-2,4-dimethyl-α-methylbenzylamine,

[0404] N-(2-methoxylbenzyl)-2,4-dimethyl-α-methylbenzylamine,

[0405] N-(4-methoxylbenzyl)-2,4-dimethyl-α-methylbenzylamine,

[0406] N-(2-ethoxylbenzyl)-2,4-dimethyl-α-methylbenzylamine,

[0407] N-(3,4-dimethoxylbenzyl)-2,4-dimethyl-α-methylbenzylamine,

[0408] N-(3-phenoxybenzyl)-2,4-dimethyl-α-methylbenzylamine,

[0409] N-(4-phenoxybenzyl)-2,4-dimethyl-α-methylbenzylamine,

[0410] N-(2-phenylbenzyl)-2,4-dimethyl-α-methylbenzylamine,

[0411] N-(3-phenylbenzyl)-2,4-dimethyl-α-methylbenzylamine,

[0412] N-(4-phenylbenzyl)-2,4-dimethyl-α-methylbenzylamine,

[0413] N-(4-methylbenzyl)-2,4-diethyl-α-methylbenzylamine,

[0414] N-(2,5-dimethylbenzyl)-2,4-diethyl-α-methylbenzylamine,

[0415] N-(2,4,6-trimethylbenzyl)-2,4-diethyl-α-methylbenzylamine,

[0416] N-(4-isopropylbenzyl)-2,4-diethyl-α-methylbenzylamine,

[0417] N-(2-methoxylbenzyl)-2,4-diethyl-α-methylbenzylamine,

[0418] N-(4-methoxylbenzyl)-2,4-diethyl-α-methylbenzylamine,

[0419] N-(2-ethoxylbenzyl)-2,4-diethyl-α-methylbenzylamine,

[0420] N-(3,4-dimethoxylbenzyl)-2,4-diethyl-α-methylbenzylamine,

[0421] N-(3-phenoxybenzyl)-2,4-diethyl-α-methylbenzylamine,

[0422] N-(4-phenoxybenzyl)-2,4-diethyl-α-methylbenzylamine,

[0423] N-(2-phenylbenzyl)-2,4-diethyl-α-methylbenzylamine,

[0424] N-(3-phenylbenzyl)-2,4-diethyl-α-methylbenzylamine,

[0425] N-(4-phenylbenzyl)-2,4-diethyl-α-methylbenzylamine, and saltsthereof with an inorganic acid such as hydrochloric acid, sulfuric acid,nitric acid or the like.

[0426] The optically active amine compound of formula (8) can be, forexample, obtained by a process, which comprises subjecting the iminecompound of formula (11) to a reduction reaction.

[0427] In the imine compound of formula (11), X₁ to X₅, R₂₂ and R₃₂respectively have the same meanings as defined for the optically activeamine compound of formula (8) above.

[0428] Specific examples of the imine compound (11) include:

[0429] N-(4-methylbenzylidene)-2-chloro-α-methylbenzylamine,

[0430] N-(2,5-dimethylbenzylidene)-2-chloro-α-methylbenzylamine,

[0431] N-(2,4,6-trimethylbenzylidene)-2-chloro-α-methylbenzylamine,

[0432] N-(4-isopropylbenzylidene)-2-chloro-α-methylbenzylamine,

[0433] N-(2-methoxylbenzylidene)-2-chloro-α-methylbenzylamine,

[0434] N-(4-methoxylbenzylidene)-2-chloro-α-methylbenzylamine,

[0435] N-(2-ethoxylbenzylidene)-2-chloro-α-methylbenzylamine,

[0436] N-(3,4-dimethoxylbenzylidene)-2-chloro-α-methylbenzylamine,

[0437] N-(3-phenoxybenzylidene)-2-chloro-α-methylbenzylamine,

[0438] N-(4-phenoxybenzylidene)-2-chloro-α-methylbenzylamine,

[0439] N-(2-phenylbenzylidene)-2-chloro-α-methylbenzylamine,

[0440] N-(3-phenylbenzylidene)-2-chloro-α-methylbenzylamine,

[0441] N-(4-phenylbenzylidene)-2-chloro-α-methylbenzylamine,

[0442] N-(4-methylbenzylidene)2,3-dichloro-α-methylbenzylamine,

[0443] N-(2,5-dimethylbenzylidene)-2,3-dichloro-α-methylbenzylamine,

[0444] N-(2,4,6-trimethylbenzylidene)-2,3-dichloro-α-methylbenzylamine,

[0445] N-(4isopropylbenzylidene)-2,3-dichloro-α-methylbenzylamine,

[0446] N-(2-methoxylbenzylidene)-2,3-dichoro-α-methylbenzylamine,

[0447] N-(4-methoxylbenzylidene)-2,3-dichloro-α-methylbenzylamine,

[0448] N-(2-ethoxylbenzylidene)-2,3-dichloro-α-methylbenzylamine,

[0449] N-(3,4-dimethoxylbenzylidene)-2,3-dichloro-α-methylbenzylamine,

[0450] N-(3-phenoxybenzylidene)-2,3-dichloro-α-methylbenzylamine,

[0451] N-(4-phenoxybenzylidene)-2,3-dichloro-α-methylbenzylamine,

[0452] N-(2-phenylbenzylidene)-2,3-dichloro-α-methylbenzylamine,

[0453] N-(3-phenylbenzylidene)-2,3-dichloro-α-methylbenzylamine,

[0454] N-(4-phenylbenzylidene)-2,3-dichloro-α-methylbenzylamine,

[0455] N-(4-methylbenzylidene)-2,4-dichoro-α-methylbenzylamine,

[0456] N-(2,5-dimethylbenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0457] N-(2,4,6-trimethylbenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0458] N-(4-isopropylbenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0459] N-(2-methoxylbenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0460] N-(4-methoxylbenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0461] N-(2-ethoxylbenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0462] N-(3,4-dimethoxylbenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0463] N-(3-phenoxybenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0464] N-(4-phenoxybenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0465] N-(2-phenylbenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0466] N-(3-phenylbenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0467] N-(4-phenylbenzylidene)-2,4-dichoro-α-methylbenzylamine,

[0468] N-(4-methylbenzylidene)-2,5-dichloro-α-methylbenzylamine,

[0469] N-(2,5-dimethylbenzylidene)-2,4-dichloro-α-methylbenzylamine,

[0470] N-(2,4,6-trimethylbenzylidene)-2,5-dichloro-α-methylbenzylamine,

[0471] N-(4-isopropylbenzylidene)-2,5-dichloro-α-methylbenzylamine,

[0472] N-(2-methoxylbenzylidene)-2,5-dichloro-α-methylbenzylamine,

[0473] N-(4-methoxylbenzylidene)-2,5-dichloro-α-methylbenzylamine,

[0474] N-(2-ethoxylbenzylidene)-2,5-dichloro-α-methylbenzylamine,

[0475] N-(3,4-dimethoxylbenzylidene)-2,5-dichloro-α-methylbenzylamine,

[0476] N-(3-phenoxybenzylidene)-2,5-dichloro-α-methylbenzylamine,

[0477] N-(4-phenoxybenzylidene)-2,5-dichloro-α-methylbenzylamine,

[0478] N-(2-phenylbenzylidenae)-2,5-dichloro-α-methylbenzylamine,

[0479] N-(3-phenylbenzylidene)-2,5-dichloro-α-methylbenzylamine,

[0480] N-(4-phenylbenzylidene)-2,5-dichloro-α-methylbenzylamine,

[0481] N-(4-methylbenzylidene)-2,6-dichloro-α-methylbenzylamine,

[0482] N-(2,5-dimethylbenzylidene)-2,6-dichloro-α-methylbenzylamine,

[0483] N-(2,4,6-trimethylbenzylidene)-2,6-dichloro-α-methylbenzylamine,

[0484] N-(4-isopropylbenzylidene)-2,6-dichloro-α-methylbenzylamine,

[0485] N-(2-methoxylbenzylidene)-2,6-dichloro-α-methylbenzylamine,

[0486] N-(4-methoxylbenzylidene)-2,6-dichoro-α-methylbenzylamine,

[0487] N-(2-ethoxylbenzylidene)-2,6-dichloro-α-methylbenzylamine,

[0488] N-(3,4-dimethoxylbenzylidene)-2,6-dichloro-α-methylbenzylamine,

[0489] N-(3-phenoxybenzylidene)-2,6-dichloro-α-methylbenzylamine,

[0490] N-(4-phenoxybenzylidene)-2,6-dichloro-α-methylbenzylamine,

[0491] N-(2-phenylbenzylidene)-2,6-dichloro-α-methylbenzylamine,

[0492] N-(3-phenylbenzylidene)-2,6-dichloro-α-methylbenzylamine,

[0493] N-(4-phenylbenzylidene)-2,6-dichloro-α-methylbenzylamine,

[0494] N-(4-methylbenzylidene)-2,4,6-trichloro-α-methylbenzylamine,

[0495] N-(2,5-dimethylbenzylidene)-2,4,6-trichloro-α-methylbenzylamine,

[0496] N-(2,4,6-triethylbenzene)-2,4,6-trichloro-α-methylbenzylamine,

[0497] N-(4-isopropylbenzylidene)-2,4,6-trichloro-α-methylbenzylamine,

[0498] N-(2-methoxylbenzylidene)-2,4,6-trichloro-α-methylbenzylamine,

[0499] N-(4-methoxylbenzylidene)-2,4,6-trichloro-α-methylbenzylamine,

[0500] N-(2-ethoxylbenzylidene)-2,4,6-trichloro-α-methylbenzylamine,

[0501]N-(3,4-dimethoxylbenzylidene)-2,4,6-trichloro-α-methylbenzylamine,

[0502] N-(3-phenoxybenzylidene)-2,4,6-trichloro-α-methylbenzylamine,

[0503] N-(4-phenoxybenzylidene)-2,4,6-trichloro-α-methylbenzylamine,

[0504] N-(2-phenylbenzylidene)-2,4,6-trichloro-α-methylbenzylamine,

[0505] N-(3-phenylbenzylidene)-2,4,6-trichloro-α-methylbenzylamine,

[0506] N-(4-phenylbenzylidene)-2,4,6-trichloro-α-methylbenzylamine,

[0507] N-(4-methylbenzylidene)-2,3,4-trichloro-α-methylbenzylamine,

[0508] N-(2,5-dimethylbenzylidene)-2,3,4-trichloro-α-methylbenzylamine,

[0509]N-(2,4,6-trimethylbenzylidene)-2,3,4-trichloro-α-methylbenzylamine,

[0510] N-(4-isopropylbenzylidene)-2,3,4-trichloro-α-methylbenzylamine,

[0511] N-(2-methoxylbenzylidene)-2,3,4-trichloro-α-methylbenzylamine,

[0512] N-(4-methoxylbenzylidene)-2,3,4-trichloro-α-methylbenzylamine,

[0513] N-(2-ethoxylbenzylidene)-2,3,4-trichloro-α-methylbenzylamine,

[0514]N-(3,4-dimethoxylbenzylidene)-2,3,4-trichloro-α-methylbenzylamine,

[0515] N-(3-phenoxybenzylidene)-2,3,4-trichloro-α-methylbenzylamine,

[0516] N-(4-phenoxybenzylidene)-2,3,4-trichloro-α-methylbenzylamine,

[0517] N-(2-phenylbenzylidene)-2,3,4-trichloro-α-methylbenzylamine,

[0518] N-(3-phenylbenzylidene)-2,3,4-trichloro-α-methylbenzylamine,

[0519] N-(4-phenylbenzylidene)-2,3,4-trichloro-α-methylbenzylamine,

[0520] N-(4-methylbenzylidene)-2,4-difluoro-α-methylbenzylamine,

[0521] N-(2,5-dimethylbenzylidene)-2,4-difluoro-α-methylbenzylamine,

[0522] N-(2,4,6-trimethylbenzylidene)-2,4-difluoro-α-methylbenzylamine,

[0523] N-(4-isopropylbenzylidene)-2,4-difluoro-α-methylbenzylamine,

[0524] N-(2-methoxylbenzylidene)-2,4-difluoro-α-methylbenzylamine,

[0525] N-(4-methoxylbenzylidene)-2,4-difluoro-α-methylbenzylamine,

[0526] N-(2-ethoxylbenzylidene)-2,4-difluoro-α-methylbenzylamine,

[0527] N-(3,4-dimethoxylbenzylidene)-2,4-difluoro-α-methylbenzylamine ,

[0528] N-(3-phenoxybenzylidene)-2,4-difluoro-α-methylbenzylamine,

[0529] N-(4-phenoxybenzylidene)-2,4-difluoro-α-methylbenzylamine,

[0530] N-(2-phenylbenzylidene)-2,4-difluoro-α-methylbenzylamine,

[0531] N-(3-phenylbenzylidene)-2,4-difluoro-α-methylbenzylamine,

[0532] N-(4-phenylbenzylidene)-2,4-difluoro-α-methylbenzylamine,

[0533] N-(4-methylbenzylidene)-2,4-dibromo-α-methylbenzylamine,

[0534] N-(2,5-dimethylbenzylidene)-2,4-dibromo-α-methylbenzylamine,

[0535] N-(2,4,6-trimethylbenzylidene)-2,4-dibromo-α-methylbenzylamine,

[0536] N-(4-isopropylbenzylidene)-2,4-dibromo-α-methylbenzylamine,

[0537] N-(2-methoxylbenzylidene)-2,4-dibromo-α-methylbenzylamine,

[0538] N-(4-methoxylbenzylidene)-2,4-dibromo-α-methylbenzylamine,

[0539] N-(2-ethoxylbenzylidene)-2,4-dibromo-α-methylbenzylamine,

[0540] N-(3,4-dimethoxylbenzylidene)-2,4-dibromo-α-methylbenzylamine,

[0541] N-(3-phenoxybenzylidene)-2,4-dibromo-α-methylbenzylamine,

[0542] N-(4-phenoxybenzylidene)-2,4-dibromo-α-methylbenzylamine,

[0543] N-(2-phenylbenzylidene)-2,4-dibromo-α-methylbenzylamine,

[0544] N-(3-phenylbenzylidene)-2,4-dibromo-α-methylbenzylamine,

[0545] N-(4-phenylbenzylidene)-2,4-dibromo-α-methylbenzylamine,

[0546] N-(4-methylbenzylidene)-2,4-diiodo-α-methylbenzylamine,

[0547] N-(2,5-dimethylbenzylidene)-2,4-diiodo-α-methylbenzylamine,

[0548] N-(2,4,6-trimethylbenzylidene)-2,4-diiodo-α-methylbenzylamine,

[0549] N-(4-isopropylbenzylidene)-2,4-diiodo-α-methylbenzylamine,

[0550] N-(2-methoxylbenzylidene)-2,4-diiodo-α-methylbenzylamine,

[0551] N-(4-methoxylbenzylidene)-2,4-diiodo-α-methylbenzylamine,

[0552] N-(2-ethoxylbenzylidene)-2,4-diiodo -α-methylbenzylamine,

[0553] N-(3,4-dimethoxylbenzylidene)-2,4-diiodo-α-methylbenzylamine,

[0554] N-(3-phenoxybenzylidene)-2,4-diiodo -α-methylbenzylamine,

[0555] N-(4-phenoxybenzylidene)-2,4-diiodo -α-methylbenzylamine,

[0556] N-(2-phenylbenzylidene)-2,4-diiodo -α-methylbenzylamine,

[0557] N-(3-phenylbenzylidene)-2,4-diiodo -α-methylbenzylamine,

[0558] N-(4-phenylbenzylidene)-2,4-diiodo -α-methylbenzylamine,

[0559] N-(4-methylbenzylidene)-2,4-dimethyl-α-methylbenzylamine,

[0560] N-(2,5-dimethylbenzylidene)-2,4-dimethyl-α-methylbenzylamine,

[0561] N-(2,4,6-trimethylbenzylidene)-2,4-dimethyl-α-methylbenzylamine,

[0562] N-(4-isopropylbenzylidene)-2,4-dimethyl-α-methylbenzylamine,

[0563] N-(2-methoxylbenzylidene)-2,4-dimethyl-α-methylbenzylamine,

[0564] N-(4-methoxylbenzylidene)-2,4-dimethyl-α-methylbenzylamine,

[0565] N-(2-ethoxylbenzylidene)-2,4-dimethyl-α-methylbenzylamine,

[0566] N-(3,4-dimethoxylbenzylidene)-2,4-dimethyl-α-methylbenzylamine,

[0567] N-(3-phenoxybenzylidene)-2,4-dimethyl-α-methylbenzylamine,

[0568] N-(4-phenoxybenzylidene)-2,4-dimethyl-α-methylbenzylamine,

[0569] N-(2-phenylbenzylidene)-2,4-dimethyl-α-methylbenzylamine,

[0570] N-(3-phenylbenzylidene)-2,4-dimethyl-α-methylbenzylamine,

[0571] N-(4-phenylbenzylidene)-2,4-dimethyl-α-methylbenzylamine,

[0572] N-(4-methylbenzylidene)-2,4-diethyl-α-methylbenzylamine,

[0573] N-(2,5-dimethylbenzylidene)-2,4-diethyl-α-methylbenzylamine,

[0574] N-(2,4,6-trimethylbenzylidene)-2,4-diethyl-α-methylbenzylamine,

[0575] N-(4-isopropylbenzylidene)-2,4-diethyl-α-methylbenzylamine,

[0576] N-(2-methoxylbenzylidene)-2,4-diethyl-α-methylbenzylamine,

[0577] N-(4-methoxylbenzylidene)-2,4-diethyl-α-methylbenzylamine,

[0578] N-(2-ethoxylbenzylidene)-2,4-diethyl-α-methylbenzylamine,

[0579] N-(3,4-dimethoxylbenzylidene)-2,4-diethyl-α-methylbenzylamine,

[0580] N-(3-phenoxybenzylidene)-2,4-diethyl-α-methylbenzylamine

[0581] N-(4-phenoxybenzylidene)-2,4-diethyl-α-methylbenzylamine,

[0582] N-(2-phenylbenzylidene)-2,4-diethyl-α-methylbenzylamine,

[0583] N-(3-phenylbenzylidene)-2,4-diethyl-α-methylbenzylamine,

[0584] N-(4-phenylbenzylidene)-2,4-diethyl-α-methylbenzylamine, and thelike.

[0585] The reduction reaction of the imine compound (11) is usuallyconducted by a process which comprises reacting the imine compound (11)with a reducing agent such as a metal hydride or the like, alternativelywith hydrogen in the presence of a catalyst.

[0586] Examples of the metal hydride include lithium aluminum hydride,sodium borohydride and borane and the like. Borane includes diborane,borane-THF, a borane-sulfide complex, a borane-amine complex and thelike.

[0587] The amount of the reducing agent to be used is usually within therange of approximately from 0.25 to 5 moles, preferably approximatelyfrom 0.25 to 2 moles per mol of the imine compound (11) in the casewhere lithium aluminum hydride or sodium borohydride is used.

[0588] When borane is used, the amount of borane to be used, on a boronebasis, is usually within the range of approximately from 0.3 to 5 moles,preferably approximately from 0.3 to 3 moles per mol of the iminecompound (11).

[0589] The reduction reaction is usually conducted in an inert solvent.Examples of the inert solvents include those as specified for thereduction reaction of the imine compound of formula (7) above.

[0590] When sodium borohydride is used as a reducing agent, a loweralcohol such as methanol, ethanol, isopropyl alcohol or the like can beused as well as the aforementioned solvents, The solvent may be usedalone or as a mixture thereof. The amount of the solvent to be used isnot particularly limited.

[0591] The reaction is usually conducted within a temperature range ofapproximately of from −50° C. to 100° C., preferably from −20° C. to100° C.

[0592] After completion of the reaction, the optically active aminecompound (8) is usually obtained, for example, by treating the resultingreaction mixture with water, acetic acid or a mineral acid, and thenbeing made alkaline, followed by extraction with a hydrophobic organicsolvent, phase separation of the organic phase and concentration thereofunder a neutral or weakly basic condition. The product may be furtherpurified by recrystallization, and/or column chromatography using silicagel, etc., if necessary.

[0593] Examples of the catalyst to be used for the reduction withhydrogen include Raney nickel, palladium-carbon, platinum dioxide,platinum black and the like.

[0594] The amount of such a catalyst to be used is usually from 0.1 to100% by weight, preferably from 0.5 to 50% by weight per 1 part byweight of the imine compound (11).

[0595] The hydrogenation reaction in the presence of a catalyst isusually conducted in an inert solvent. Examples of the solvent includethose as specified for the reduction reaction of the imine compound offormula (7) above. The amount of the solvent to be used is notparticularly limited.

[0596] The hydrogenation is usually conducted within the range ofapproximately from −30° C. to 150° C., preferably from −10° C. to 100°C.

[0597] The hydrogenation is usually conducted at a pressure ofapproximately from 0 to 10 MPa (0 to 100 kg/cm²), preferablyapproximately from 0 to 5 MPa (0 to 50 kg/cm²).

[0598] After completion of the reaction, the optically active aminecompound (8) can be obtained, for example, by removing the catalyst byfiltration, followed by concentrating the filtrate. The desired productmay be further purified by recrystallization and/or columnchromatography using silica gel, if necessary.

[0599] Then imine compound of formula (11) can be obtained, for example,by a process which comprises reacting the aldehyde compound of formula(10) with an optically active amine compound of formula (9).

[0600] Examples of the aldehyde compound of formula (10) include4-methylbenzaldehyde, 2,5-dimethylbenzaldehyde,2,4,6-trimethylbenzaldehyde, 4-isopropylbenzaldehyde,2-methoxybenzaldehyde, 4-methoxybenzaldehyde, 2-ethoxybenzaldehyde,3,4-dimethylbenzaldehyde, 5-fluoro-2-methoxybenzaldehyde,3-phenoxybenzaldehyde, 4-phenoxybenzaldehyde, 2-phenylbenzaldehyde,3-phenylbenzaldehyde, 4-phenylbenzaldehyde, and the like. Thesealdehydes are commercially available or may be obtained by a similarmanner as disclosed in references such as Houben-Weyl, Methoden derOrganischen Chemie, Georg-Thieme-Verlag, Stuttgart and the like.

[0601] Examples of the optically active amine compound of formula (9)include 2,4-dichloro-α-methylbenzylamine and the like.

[0602] The optically active amine (9) is usually reacted with thebenzaldehyde of formula (10) in a solvent. Examples of the solventinclude those specified above for the reaction of the optically activeamine compound of formula (5) with the benzyloxybenzaldehyde (6).

[0603] The optically active amine (9) are commercially available or canbe obtained by a similar manner as disclosed in references such asHouben-Weyl, Methoden der Organischen Chemie, Georg-Thieme-Verlag,Stuttgart and the like.

[0604] The amount of the benzaldehyde (10) is usually 1 to 1.2 moles permole of the optically active amine (9).

[0605] The reaction is usually conducted within the range of from 0° C.to 200° C., preferably from 0° C. to 150° C.

[0606] Although the obtained imine compound (11) can be isolated, forexample, by evaporation and the like, it may be used, as it is, in thesubsequent reaction without being isolated.

EXAMPLES

[0607] The present invention will be explained by the followingexamples, but it is not to be construed to limit the present inventionthereto.

[0608] In the following examples, optical purities were determined byhigh performance liquid chromatography.

Example 1

[0609] In 2.96 g of t-butyl methyl ether, 148 mg (0.94 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid was dissolved at 55° C.To this solution was added, at that temperature, a solution prepared bydissolving in advance 136 mg (0.45 mmol) of(S)-N-benzyl-1-phenyl-2-(p-tolyl)ethylamine in 2.96 g of t-butyl methylether, and then stirred to mix.

[0610] After ascertaining the precipitation of crystals, the mixture wascooled gradually to 20° C. over 3 hours with stirring.

[0611] The crystals formed were collected by filtration, washed with2.96 g of t-butyl methyl ether and then dried to yield 87 mg of(S)-N-benzyl-1-phenyl-2-(p-tolyl)ethylamine salt of(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 95% ee. Melting point: 163 to 164° C.; Specific rotation[α]_(D) ²⁵=+62° (c=0.55, methanol)

Example 2

[0612] In 0.79 g of acetone, 148 mg (0.93 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid was dissolved at 20° C.To this solution was added, at that temperature, a solution prepared bydissolving in advance 135 mg (0.45 mmol) of(S)-N-benzyl-1-phenyl-2-(p-tolyl)ethylamine in 0.79 g of acetone, andthen stirred to mix.

[0613] The solution after mixing was left standing at 20° C. for 18hours to precipitate crystals.

[0614] The crystals formed were collected by filtration, washed with0.79 g of acetone and then dried to yield 17 mg of(S)-N-benzyl-1-phenyl-2-(p-tolyl)ethylamine salt of(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 99% ee.

Example 3

[0615] In 0.78 g of acetonitrile, 147 mg (0.93 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid was dissolved at 20° C.To this solution was added, at that temperature, a solution prepared bydissolving in advance 135 mg (0.45 mmol) of(S)-N-benzyl-phenyl-2-(p-tolyl)ethylamine in 0.78 g of acetonitrile, andthen stirred to mix.

[0616] The solution after mixing was left standing at 20° C. for 18hours to precipitate crystals.

[0617] The crystals formed were collected by filtration, washed with1.56 g of acetonitrile and then dried to yield 50 mg of(S)-N-benzyl-1-phenyl-2-(p-tolyl)ethylamine salt of(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 96% ee.

Example 4

[0618] In 2.96 g of t-butyl methyl ether, 157 mg (1.00 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid was dissolved at 55° C.To this solution was added, at that temperature, a solution prepared bydissolving in advance 152 mg (1.00 mmol) of (1R,2S)-(−)-norephedrine in2.96 g of t-butyl methyl ether, and then stirred to mix.

[0619] After ascertaining the precipitation of crystals, the mixture wascooled gradually to 20° C. over 3 hours with stirring. The crystalsformed were collected by filtration, washed with 1.48 g of t-butylmethyl ether and then dried to yield 77 mg of (1R,2S)-(−)-norephedrinesalt of (S)3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with anoptical purity of 78% ee. Melting point: 149 to 150° C.; Specificrotation [α]_(D) ²⁵=−33° (c=0.37, methanol)

Example 5

[0620] In a mixed solvent of 0.17 g of n-butanol and 0.87 g of toluene,149 mg (0.94 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid was dissolved at 50° C.To this solution was added, at that temperature, a solution prepared bydissolving in advance 148 mg (0.98 mmol) of (1R,2S)-(−)-norephedrine ina mixed solvent of 0.17 g of n-butanol and 0.87 g of toluene, and thenstirred to mix.

[0621] After ascertaining the precipitation of crystals, the mixture wascooled gradually to 20° C. over 3 hours with stirring.

[0622] The crystals formed were collected by filtration, washed with amixed solvent of 0.35 g of n-butanol and 1.73 g of toluene and thendried to yield 78 mg of (1R,2S)-(−)-norephedrine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 84% ee.

Example 6

[0623] In 1.48 g of t-butyl methyl ether, 159 mg (1.01 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid was dissolved at 45° C.To this solution was added, at that temperature, a solution prepared bydissolving in advance 172 mg (0.54 mmol) of(S)-N-(3-benzyloxybenzyl)-α-methylbenzylamine in 1.48 g of t-butylmethyl ether, and then stirred to mix. After ascertaining theprecipitation of crystals, the mixture was cooled gradually to 35° C.over 0.5 hour with stirring

[0624] The crystals formed were collected by filtration, washed with2.96 g of t-butyl methyl ether and then dried to yield 61 mg of(S)-N-(3-benzyloxybenzyl)-α-methylbenzylamine salt of(R)-3,3,3-trifluoro-2-hydroxy. 2-methylpropionic acid with an opticalpurity of 95% ee. Melting point: 131 to 132° C.; Specific rotation[α]_(D) ²⁵=−5.8° (c=0.59, methanol)

Example 7

[0625] In 4.77 g of 2-propanol, 4.77 g (15.8 mmol) of(S)-N-benzyl-1-phenyl-2-(p-tolyl) ethylamine was dissolved at 50° C. Tothis solution was added, at that temperature, a solution prepared bydissolving in advance 5.04, (31.9 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid in 10.1 g of t-butylmethyl ether, and then stirred to mix.

[0626] After ascertaining the precipitation of crystals, the mixture wascooled gradually to 0° C. over 3 hours with stirring, and thereafterheld at that temperature for 2 hours.

[0627] The crystals formed were collected by filtration, washed with 35g of 0° C. t-butyl methyl ether and then dried to yield 5.57 g of(S)-N-benzyl-1-phenyl-2-(p-tolyl)ethylamine salt of(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 91% ee.

Example 8

[0628] In 29.1 g of toluene, 4.77 g (15.8 mmol) of(S)-N-benzyl-1-phenyl-2-(p-tolyl) ethylamine was dissolved at 60° C. Tothis solution was added, at that temperature, a solution prepared bydissolving in advance 5.04 g (31.9 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid in 10.1 g of t-butylmethyl ether, and then stirred to mix.

[0629] After cooling to room temperature, a seed crystal was inoculated.After ascertaining the precipitation of crystals, the mixture wasstirred overnight at room temperature, and subsequently cooled graduallyto 0° C. over 2 hours with stirring.

[0630] The crystals formed were collected by filtration, washed with 13g of 0° C. toluene and then dried to yield 4.12 g of(S)-N-benzyl-1-phenyl-2-(p-tolyl)ethylamine salt of(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 94% ee.

Example 9

[0631] In 5.0 g of toluene, 0.48 g (1.04 mmol) of the(S)-N-benzyl-1-phenyl-2-(p-tolyl)ethylamine salt of(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 91% ee which was obtained in Example 7 was dissolved at 60°C., and then cooled gradually to 20° C. with stirring

[0632] The crystals formed were collected by filtration, washed with 2.0g of toluene and then dried to yield 0.42 g of(S)-N-benzyl-1-phenyl-2-(p-tolyl)ethylamine salt of(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 99% ee.

Example 10

[0633] In ethanol, 4.90 g (10.7 mmol) of the(S)-N-benzyl-1-phenyl-2-(p-tolyl)ethylamine salt of(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 91% ee which was obtained in Example 7 was dissolved at 60°C., and then cooled gradually to 0° C. with stirring.

[0634] The crystals formed were collected by filtration, washed withethanol and then dried to yield 3.80 g of(S)-N-benzyl-1-phenyl-2-(p-tolyl)ethylamine salt of(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 98% ee.

Example 11

[0635] In 10.3 g of methanol, 3.50 g (7.62 mmol) of the(S)-N-benzyl-1-phenyl-2-(p-tolyl)ethylamine salt of(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 94% ee which was obtained in Example 8 was dissolved at 60°C., inoculated at 50° C., and then cooled gradually to 0° C. over 5hours with stirring.

[0636] The crystals formed were collected by filtration, washed with 7.4g of 0° C. methanol and then dried to yield 2.81 g of(S)-N-benzyl-1-phenyl-2-(p-tolyl)ethylamine salt of(P)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of >99% ee.

Example 12

[0637] To 22 mg (0.05 mmol) of the salt obtained in Example 1, 2 ml of a2N aqueous sodium hydroxide solution and 5 ml of t-butyl methyl etherwere added and the salt was completely dissolved. The aqueous layer wasthen isolated.

[0638] Subsequently, to the isolated aqueous layer, 5 ml of a 2Nhydrochloric acid solution and 5 ml of t-butyl methyl ether were addedand stirred, followed by isolating the t-butyl methyl ether layer. Theisolated t-butyl methyl ether solution was concentrated under reducedpressure to remove the solvent so as to precipitate a solid. Theprecipitated solid was washed with 0.5 ml of n-hexane, isolated byfiltration and then dried to yield 7 mg of(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 95% ee.

Example 13

[0639] A solution of 151 mg (0.96 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid in 0.74 g of t-butylmethyl ether was added at 25° C. to a solution of 189 mg (0.53 mmol) of(R)-N-(4-phenylbenzyl)-2,4-dichlorobenzylamine in 0.74 g of t-butylmethyl ether, and the resulting solution was mixed under stirring. Drynitrogen gas was blown onto the surface of the solution to concentratethe solution so as to precipitate crystals. The precipitated crystalswere washed with 0.74 g of t-butyl methyl ether and the crystals werecollected by filtration and the collected crystals were washed with 0.74g of t-butyl methyl ether and dried to yield 166 mg of(R)-N-(4-phenylbenzyl) -2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 86% ee.

Example 14

[0640] A solution of 166 mg (1.05 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid in 0.74 g of t-butylmethyl ether was added at 25° C. to a solution of 205 mg (0.54 mmol) of(S)-N-(4-phenylbenzyl)-1-phenyl-2-(p-tolyl)ethylamine in 0.74 g oft-butyl methyl ether, and the resulting solution was mixed understirring. The solution was left standing at the same temperature for 1day to precipitate crystals. The precipitated crystals were washed with0.74 g of t-butyl methyl ether and the crystals were collected byfiltration and the collected crystals were washed with 0.74 g of t-butylmethyl ether and dried to yield 203 mg of (S)-N-(4-phenylbenzyl)1-phenyl-2-(p-tolyl)ethylamine salt of(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 72% ee.

[0641] Melting point: 168 to 170° C.; Specific rotation [α]_(D) ²⁵=+46°(c=0.80, methanol)

Example 15

[0642] A solution of 154 mg (0.97 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid in 0.74 g of t-butylmethyl ether was added at 25° C. to a solution of 195 mg (0.50 mmol) of(R)-N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine in 0.74 g oft-butyl methyl ether, and the resulting solution was mixed understirring. The solution was left standing at 5° C. for 1 day toprecipitate crystals. The precipitated crystals were washed with 0.74 gof t-butyl methyl ether and dried to yield 216 mg of(R)-N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 61% ee.

Example 16

[0643] A solution of 164 mg (1.04 mmol) of racemic3,3,3-trifluoro-2-hyrdroxy-2-methylpropiopic acid dissolved in 0.78 g ofacetonitrile at 55° C. was added at the same temperature to a solutionof 157 mg (0.56 mmol) of (R)-N-benzyl-2,4-dichloro-α-methylbenzylaminedissolved in 0.78 of acetonitrile at 55° C., and the resulting solutionwas mixed under stirring. The solution was inoculated at 40° C. andcooled to 25° C. under stirring over 3 hours. The precipitated crystalswere washed with 0.78 g of acetonitrile and dried to yield 65 mg of(R)-N-benzyl-2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 98% ee.

Example 17

[0644] A solution of 163 mg (1.03 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid dissolved in 0.89 g ofethyl acetate at 55° C. was added at the same temperature to a solutionof 160 mg (0.57 mmol) of R)-N-benzyl-2,4-dichloro-α-methylbenzylaminedissolved in 0.89 g of ethyl acetate at 55° C., and the resultingsolution was mixed under stirring. The solution was inoculated at 10° C.After confirming precipitation, stirring was continued for 16 hours at10° C. The precipitated crystals were collected by filtration and washedwith 0.89 g of ethyl acetate to yield 42 mg of(R)-N-benzyl-2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of >99% ee.

Example 18

[0645] A solution of 159 mg (1.00 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid dissolved in a mixedsolvent of 0.50 g of water and 0.40 g of 2-propanol at 55° C. was addedat the same temperature to a solution of 159 mg (0.57 mmol) of(R)-N-benzyl-2,4-dichloro-α-methylbenzylamine dissolved in a mixedsolvent of 0.50 g of water and 0.40 g of 2-propanol at 55° C., and theresulting solution was mixed under stirring. The solution was inoculatedat 40° C. and cooled to 25° C. under stirring over 3 hours. Theprecipitated crystals were collected by filtration and washed with amixed solution of 0.50 g of water and 0.40 g of 2-propanol and dried toyield 109 mg of (R)-N-benzyl-2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 97% ee.

[0646] Melting point: 152 to 154° C.; Specific rotation [α]_(D) ²⁵=−24°(c=0.62, methanol)

Example 19

[0647] A solution of 164 mg (1.04 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid dissolved in 2.22 g oft-butyl methyl ether at 55° C. was added at 65° C. to a solution of 180mg (0.51 mmol) of(R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine in 2.22 g oft-butyl methyl ether, and the resulting solution was mixed understirring. The solution was inoculated at 55° C. and then cooled to 25°C. under stirring over 1 hour. The precipitated crystals were collectedby filtration and the collected crystals were washed with 0.74 g oft-butyl methyl ether and dried to yield 144 mg of(R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 97% ee.

Example 20

[0648] A solution of 163 mg (1.03 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid dissolved in 0.78 g ofacetonitorile at 55° C. was added at 55° C. to a solution of 184 mg(0.52 mmol) of (R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylaminein 0.78 of acetonitorile and the resulting solution was mixed understirring. The solution was inoculated at 55° C. and then cooled to 25°C. under stirring over 1 hour. The precipitated crystals were collectedby filtration and the collected crystals were washed with 0.78 g ofacetonitorile and dried to yield 149 mg of(R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 97% ee.

Example 21

[0649] A solution of 161 mg (1.02 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid dissolved in 0.86 g oftoluene at 55° C. was added at 55° C. to a solution of 189 mg (0.53mmol) of (R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine in 0.86g of toluene and the resulting solution was mixed under stirring. Thesolution was inoculated at 40° C. and then cooled to 25° C. understirring over 0.5 hour. The precipitated crystals were collected byfiltration and the collected crystals were washed with 0.86 g of tolueneand dried to yield 59 mg of(R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 99% ee.

Example 22

[0650] A solution of 165 mg (1.04 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid dissolved in 0.78 g ofacetone at 55° C. was added at 55° C. to a solution of 177 mg (0.49mmol) of (R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine in 0.78g of acetone and the resulting solution was mixed under stirring. Thesolution was inoculated at 40° C. and then cooled to 25° C. understirring over 0.5 hour. The precipitated crystals were collected byfiltration and the collected crystals were washed with 0.78 g of acetoneand dried to yield 88 mg of(R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 99% ee or more.

Example 23

[0651] A solution of 166 mg (1.05 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid dissolved in 0.89 g ofethyl acetate at 55° C. was added at 55° C. to a solution of 190 mg(0.53 mmol) of (R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylaminein 0.89 g of ethyl acetate and the resulting solution was mixed understirring. The solution was inoculated at 55° C. and then cooled to 25°C. under stirring over 1 hour. The precipitated crystals were collectedby filtration and the collected crystals were washed with 0.89 g ofethyl acetate and dried to yield 116 m.g of(R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 99% ee.

Example 24

[0652] A solution of 172 mg (1.09 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid dissolved in 2.22 g oft-butyl methyl ether at 55° C. was added at 55° C. to a solution of 192mg (0.50 mmol) of(R)-N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine in 2.22 g oft-butyl methyl ether and the resulting solution was mixed understirring. The solution was inoculated at 56° C. and then cooled to 25°C. under stirring over 1 hour. The precipitated crystals were collectedby filtration and the collected crystals were washed with 0.74 g oft-butyl methyl ether and dried to yield 201 mg of(R)-N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 97% ee.

Example 25

[0653] A solution of 165 mg (1.05 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid dissolved in 0.78 g ofacetonitorile at 55° C. was added at 55° C. to a solution of 194 mg(0.50 mmol) of(R)-N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine in 0.78 g ofin acetonitrile and the resulting solution was mixed under stirring. Thesolution was inoculated at 26° C. to precipitate. Then, the precipitatedcrystals were collected by filtration and the collected crystals werewashed with 0.78 g of acetonitorile and dried to yield 77 mg of(R)-N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 99% ee.

Example 26

[0654] A solution of 2.46 g (15.56 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid dissolved in a mixedsolvent of 20.82 g of water and 16.65 g of 2-propanol at 55° C. wasadded at 55° C. to a solution of 2.80 g (7.85 mmol) of(R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine in a mixedsolvent of 20.78 g of water and 16.62 g of 2-propanol and the resultingsolution was mixed under stirring. The solution was inoculated at 55° C.and then cooled to 25° C. under stirring over 1.5 hours and kept at thetemperature for 2 hours. The precipitated crystals were collected byfiltration and the collected crystals were washed with a mixed solventof 2.50 of water and 2.00 g of 2-propanol and dried to yield 2.75 g of(R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 97% ee. Melting point: 168 to 170° C.; Specific rotation[α]D25=−18° (c=0.88, methanol)

Example 27

[0655] A solution of 2.50 g (15.79 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid dissolved in a mixedsolvent of 9.63 g of water and 7.72 g of 2-propanol at 55° C. was addedat 55° C. to a solution of 2.12 g (5.48 mmol) of(R)-N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine in a mixedsolvent of 9.74 g of water and 7.78 g of 2-propanol and the resultingsolution was mixed under stirring. The solution was inoculated at 55° C.and then cooled to 25° C. under stirring over 1.5 hours and kept at thetemperature for 1 day. The precipitated crystals were collected byfiltration and the collected crystals were washed with a mixed solventof 2.50 g of water and 2.00 g of 2-propanol and dried to yield 2.38 g of(R)-N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 98% ee.

[0656] Melting point: 142 to 144° C.; Specific rotation [α]D25=−16°(c=0.80, methanol)

Example 28

[0657] In 600 ml of ethanol, 27.19 g (0.224 mol) of(S)-α-methylbenzylamine and 50.00 g (0.236 mol) of3-benzyloxybenzaldehyde were stirred at room temperature for 8 hours.After ascertaining the disappearance of the amine, 8.15 g (0.215 mol) ofsodium borohydride was added at room temperature and stirred at 30° C.to 35° C. for 8 hours.

[0658] After the reaction, 185.00 g of 10% hydrochloric acid was addedat room temperature. The resulting mixture was then concentrated underreduced pressure. The residue was dissolved in 700 ml of water andwashes with 500 ml of diethyl ether.

[0659] The resulting aqueous layer was adjusted to pH>10 with a 20%aqueous sodium hydroxide solution and extracted with 500 ml of toluene,which was then washed with 250 ml of water and concentrated underreduced pressure to yield 54.71 g (0.172 mol) of(S)-N-(3-benzyloxybenzyl)-α-methylbenzylamine. (Yield: 77.4%; Purity:99.5%)

[0660] NMR spectrum data (δ ppm, CDCl₃)

[0661] 1.34 (d) 2H; 1.54 (s) 1H; 3.61 (q) 2H; 3.79 (q) 1H; 5.06 (s) 2H;6.83-7.46 (m) 14H.

Example 29

[0662] Following the procedure of Example 28 except for using4-benzyloxybenzaldehyde in place of 3-benzyloxybenzaldehyde, operationswere conducted.

[0663] (S)-N-(4-benzyloxybenzyl)-α-methylbenzylamine was obtained in anamount of 57.3 g (0.181 mol). (Yield: 80.4%; Purity: 99.3%)

[0664] NMR spectrum data (δ ppm, CDCl₃)

[0665] 1.34 (d) 2H; 1.48 (s) 1H; 3.55 (q) 2H; 3.78 (q) 1H; 5.05 (s) 2H;6.90-7.45 (m) 14H.

Example 30

[0666] 7.48 g (0.0394 mol) of (R)-2,4-dichloro-α-methylbenzylamine and10.03 g (0.0473 mol) of 3-benzyloxybenzaldehyde were mixed in a mixedsolvent of 50 ml of t-butyl methyl ether and 10 ml of methanol understirring at room temperature for 8 hours. After ascertaining thedisappearance of the amine, 20 ml of methanol was added thereto and 2.63g (0.0695 mol) of sodium borohydride was added at room temperature andstirred at that temperature for 13 hours.

[0667] After the reaction, 13 ml of 36% hydrochloric acid and 10 ml ofwater were added at room temperature. The resulting mixture was thenconcentrated under reduced pressure. The liquid residue was dissolved in25 ml of t-butyl methyl ether under stirring and then left standing toprecipitate, which was removed by filtration. To the obtained filtratewas made alkaline by adding a solution of 21.35 g of sodium hydroxidedissolved in 200 ml of water and the resulting solution was subjected toextraction with 500 ml of t-butyl methyl ether. The extract wasevaporated to yield 14.51 g (0.0376 mol) of crude(R)-N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine.(Yield:95.5%, Purity 80.8%)

[0668] To 14.51 g (0.0376 mol) of crude(R)-N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine obtained wereadded 4 ml of 36% hydrochloric acid and 30 ml of t-butyl methyl ether,the resulting solution was left standing at room temperature for 2 daysto precipitate. The precipitated crystals were separated by filtrationand washed with 25 ml of t-butyl methyl ether. Then the crystals werecontacted with an alkaline solution of 1.84 g of sodium hydroxide in 50ml of water, and extracted with 300 ml of t-butyl methyl ether underalkaline condition. The extract was evaporated under reduced pressure toyield 5.62 g (0.0145 mol) of purified(R)-N-(3-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine. (Yield:37.0%, Purity 99.8%)

[0669] NMR spectrum data (δ ppm, CDCl₃)

[0670] 1.30 (d) 3H; 1.57 (s) 1H; 3.57 (d) 2H; 4.27 (q) 1H; 5.05 (s) 2H;7.20-7.58 (m) 12H.

Example 31

[0671] 7.34 g (0.0386 mol) of (R)-2,4-dichloro-α-methylbenzylamine and9.73 g (0.0458 mol) of 4-benzyloxybenzaldehyde were mixed in a mixedsolvent of 50 ml of t-butyl methyl ether and 20 ml of methanol andstirred at room temperature for 9 hours. After ascertaining thedisappearance of the amine, 1.75 g (0.0463 mol) of sodium borohydridewas added thereto at room temperature and stirred at that temperaturefor 5 hours.

[0672] After the reaction, 13 ml of 36% hydrochloric acid and 30 ml ofwater were added at room temperature. Precipitated crystals werecollected by filtration and washed with 25 ml of t-butyl methyl ether.Then the crystals were mixed with alkaline solution containing 2.93 ofsodium hydroxide in 100 ml of water and extracted with 900 ml of t-butylmethyl ether under alkaline condition. The extract was evaporated underreduced pressure to yield 12.53 g (0.0324 mol) of purified(R)-N-(4-benzyloxybenzyl)-2,4-dichloro-α-methylbenzylamine. (Yield:84.0%, Purity 99.4%)

[0673] NMR spectrum data (δ ppm, CDCl₃)

[0674] 1.30 (d) 3H; 1.63 (s) 1H; 3.52 (s) 2H; 4.27 (q) 1H; 5.04 (s) 2H;6.88-7.58 (m) 12H.

Example 32

[0675] 7.24 g (0.0381 mol) of (R)-2,4-dichloro-α-methylbenzylamine and9.06 g (0.0457 mol) of 3-phenoxybenzaldehyde were mixed in 100 ml ofethanol and stirred at room temperature for 6 hours. After ascertainingthe disappearance of the amine, 1.75 g (0.0463 mol) of sodiumborohydride was added thereto at room temperature and stirred at thattemperature for 3 hours.

[0676] After the reaction, 10 ml of 36% hydrochloric acid and 10 ml ofwater were added at room temperature and evaporated under reducedpressure. To the obtained residue were added 100 ml of t-butyl methylether and 100 ml of water and stirred. The solution was left standing toprecipitate. Precipitated crystals were washed with 100 ml of t-butylmethyl ether and then mixed with alkaline solution containing 6.98 g ofsodium hydroxide in 100 ml of water and made alkaline and extracted with150 ml of chloroform under alkaline condition. The extract wasevaporated under reduced pressure to yield 13.5 g (0.0361 mol) of puried(R)-N-(3-phenoxybenzyl)-2,4-dichloro-α-methylbenzylamine. (Yield: 94.8%,Purity 94.1%)

[0677] NMR spectrum data (δ ppm, CDCl₃)

[0678] 1.29 (d) 3H; 1.58 (s) 1H; 3.57 (d) 2H; 4.25 (q) 1H; 6.95-7.56 (m)12H.

Example 33

[0679] 7.06 g (37.1 mol) of [R)-2,4-dichloro-α-methylbenzylamine and8.13 g (44.6 mmol) of 4-phenylbenzaldehyde were mixed in 50 ml oft-butyl methyl ether and stirred at room temperature for 1 hour. Afterascertaining the disappearance of the amine, 30 ml of methanol was addedthereto and 2.60 g (68.7 mmol) of sodium borohydride was gradually addedat room temperature and stirred at room temperature for 16 hours.

[0680] After the reaction, 13 ml of 36% hydrochloric acid and 10 ml ofwater were added at room temperature and evaporated under reducedpressure to yield crystals. To the obtained crystals was added 25 ml oft-butyl methyl ether, stirred and separated the crystals by filtration.The crystals were washed with 50 ml of t-butyl methyl ether and thenmixed with alkaline solution containing 2.87 g of sodium hydroxide in100 ml of water and extracted with 800 ml of t-butyl methyl ether underalkaline condition. The extract was evaporated under reduced pressure toyield 9.65 g (27.1 mmol) of(R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine. (Yield: 72.9%,Purity 99.1%)

[0681] NMR spectrum data (δ ppm, CDCl₃)

[0682] 1.34 (d) 3H; 1.60 (s) 1H; 3.64 (8) 2H; 4.32 (q) 1H; 7.25-7.62 (m)12H:.

Example 34

[0683] 0.12 g (0.97 mmol) of (S)-α-methylbenzylamine and 0.25 g (1.19mmol) of 3-benzyloxybenzaldehyde are mixed in 4 ml of t-butyl methylether and stirred for three days at room temperature, and thenevaporated under reduced pressure to give 0.35 g (1.12 mmol) of(S)-N-(3-benzyloxybenzylidene)-α-methylbenzylamine (Yield: 115%, purity85%).

[0684] NMR spectrum data (δ ppm, CDCl₃)

[0685] 1.58 (d) 3S; 4.54 (q) 1H; 5.10 (s) 2H; 7.04-7.50 (m) 14H; 8.33(s) 1H.

Example 35

[0686] 0.11 g (0.93 mmol) of (S)-α-methylbenzylamine and 0.26 g (1.23mmol) of 4-benzyloxybenzaldehyde are mixed in 4 ml of t-butyl methylether and stirred for three days at room temperature, and thenevaporated under reduced pressure to give a residue, which was thenwashed with 5 ml of n-hexane, filtered, and dried to give 0.24 g (0.77mmol) of (S)-N-(4-benzyloxybenzylidene)-α-methylbenzylamine (Yield: 83%,purity 90%).

[0687] NMR spectrum data (δ ppm, CDCl₃)

[0688] 1.57 (d) 3H; 4.50 (q) 1H; 5.08 (s) 2H; 6.97-7.84 (m) 14H; 8.29(s) 1H.

Example 36

[0689] In Example 34 (R)-2,4-dichloro-α-methylbenzylamine was used inplace of (S)-α-methylbenzylamine and similar operations were conductedto obtain 0.43 g (1.11 mmol) of(R)-N-(3-benzyloxybenzylidene)-2,4-dichloro-α-methylbenzylamine (Yield:109%, Purity: 90%)

[0690] NMR spectrum data (δ ppm, CDCl₃)

[0691] 1.51 (d) 3H; 4.92 (q) 1H; 5.10 (s) 2H; 7.02-7.74 (m) 12H; 8.35(s) 1H.

Example 37

[0692] In Example 36 4-benzyloxybenzaldehyde was used in place of3-benzyloxybenzaldehyde and similar operations were conducted to obtain0.47 g (1.23 mmol) of(R)-N-(4-benzyloxybenzylidene)-2,4-dichloro-α-methylbenzylamine (Yield:100%, Purity: 98%)

[0693] NMR spectrum data (δ ppm, CDCl₃)

[0694] 1.49 (d) 3H; 4.88 (q) 1H; 5.09 (s) 2H; 6.98-7.74 (m) 12H; 8.31(s) 1H.

Example 38

[0695] In Example 36 4-phenylbenzaldehyde was used in place of3-benzyloxybenzaldehyde and similar operations were conducted to obtain0.391 g (1.10 mmol) of(R)-N-(4-phenylbenzylidene)-2,4-dichloro-α-methylbenzylamine (Yield:113%, Purity: 89%)

[0696] NMR spectrum data (δ ppm, CDCl₃)

[0697] 1.53 (d) 3H; 4.95 (q) 1H; 7.23-7.86 (m) 12H; 8.42 (s) 1H.

Example 39

[0698] In Example 36 3-phenoxybenzaldehyde was used in place of3-benzyloxybenzaldehyde and similar operations were conducted to obtain0.420 g (1.13 mmol) of(R)-N-(3-phenoxybenzylidene)-2,4-dichloro-α-methylbenzylamine (Yield:116%, Purity: 86%)

[0699] NMR spectrum data (δ ppm, CDCl₃)

[0700] 1.50 (d) 3R; 4.92 (q) 1H; 7.00-7.71 (m) 12H; 8.34 (s) 1H.

Comparative Example 1

[0701] In 2.37 g of methanol, 153 mg (0.96 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid was dissolved at 45° C.To this solution was added, at that temperature, a solution prepared bydissolving in advance 200 mg (0.51 mmol) of (−)-brucine in 2.37 g ofmethanol, and then stirred to mix.

[0702] The solution after mixing was left standing at room temperaturefor 2 days to precipitate crystals.

[0703] The crystals formed were collected by filtration, washed with3.17 g of methanol and then dried to yield 115 mg of (−)-brucine salt of(S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an opticalpurity of 42% ee.

Comparative Example 2

[0704] In 1.48 g of t-butyl methyl ether, 310 mg (1.96 mmol) of racemic3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid was dissolved at roomtemperature. To this solution was added, at that temperature, a solutionprepared by dissolving in advance 235 mg (1.94 mmol) of(S)-α-methylbenzylamine in 1.48 g of t-butyl methyl ether, and thenstirred to mix.

[0705] The solution was left standing thereafter for 3 days at 5° C.,and resulted in no precipitation of crystals, the solvent was removed byblowing nitrogen onto the surface of the solution at room temperature toconcentrate the solution so as to precipitate crystals.

[0706] The crystals formed were collected by filtration, washed with1.48 g of t-butyl methyl ether and Men dried to yield 253 mg of(S)-α-methylbenzylamine salt of(S)-3,3,3-trifluoro)-2-hydroxy-2-methylpropionic acid with an opticalpurity of 5% ee.

What is claimed is:
 1. An optically active amine compound of formula (4):

wherein an asymmetric carbon atom denoted by the symbol * is in S configuration or R configuration, R₁₁ represents an aryl group which may be substituted with at least one group selected from a C1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group and a halogen atom, R₂₁ represents a C1-C4 alkyl group, or an aralkyl group which may be substituted, and R₃₁ is a 3-benzyloxyphenyl group or a 4-benzyloxyphenyl group, or a salt thereof.
 2. The optically active amine compound of formula (4) according to claim 1, wherein R₁₁ represents a phenyl or a naphthyl group which may be substituted with at least one group selected from a C1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group and a halogen atom, R₂₁ represents a C1-C4 alkyl group, or a C7-C12 aralkyl group, of which aryl group may be substituted with at least one group selected from a C1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group, a halogen atom, a C6-C10 aryl group, a C6-C10 aryloxy group, a C7-C12 aralkyl group and a C7-C12 aralkyloxy group, the last four of which may be substituted on each aromatic ring with at least one group selected from a C1-C4 alkyl group, a C1-C4 alkoxy group and a halogen atom, and of which alkyl group may be substituted with a hydroxyl group.
 3. The optically active amine compound, or a salt thereof according to claim 2, wherein R₁₁ is a phenyl group and R₂₁ is a methyl group.
 4. The optically active amine compound, or a salt thereof according to claim 2, wherein R₁₁ is a 2,4-dichlorophenyl group and R₂₁ is a methyl group.
 5. A method for producing an optically active amine compound of formula (4):

wherein an asymmetric carbon atom denoted by the symbol * is in S configuration or R configuration, R₁₁ represents an aryl group which may be substituted with at least one group selected from a C1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group and a halogen atom, R₂₁ represents a C1-C4 alkyl group, or an aralkyl group which may be substituted, and R₃₁ represents a 3-benzyloxyphenyl group or a 4-benzyloxyphenyl group, or a salt thereof, which comprises subjecting an imine compound of formula (7):

wherein the symbol *, R₁₁, R₂₁ and R₃₁ respectively have the same meaning as defined above, to a reduction reaction.
 6. An imine compound of formula (7):

wherein an asymmetric carbon atom denoted by the symbol * is in S configuration or R configuration, R₁₁ represents an aryl group which may be substituted with at least one group selected from a C1-C4 alkyl group, a C1-C4 alkoxy group, a nitro group and a halogen atom, R₂₁ represents a C1-C4 alkyl group, or an aralkyl group which may be substituted, and R₃₁ represents a 3-benzyloxyphenyl group or a 4-benzyloxyphenyl group.
 7. A method for producing an imine compound of formula (7):

wherein the symbol *, R₁₁, R₂₁, and R₃₁ respectively have the same meaning as defined in claim 14, which comprises reacting an optically active amine of formula (5):

wherein the symbol * denotes an asymmetric carbon atom, and R₁₁ and R₂₁ respectively represent the same as defined in connection with the imine compound of formula (7), with a benzyloxybenzaldehyde of formula (6): R₃₁—CHO   (6), wherein R₃₁ represents the same as defined in connection with the imine compound of formula (7).
 8. An optically active amine compound of formula (8):

wherein X₁ represents a halogen atom, a lower alkyl group, X₂ to X₅ are the same or different an independently represent a hydrogen atom, a halogen atom, a nitro group or a lower alkyl group, R₂₂ represents a lower alkyl group, and R₃₂ represents an aryl group substituted with at least one group selected from a lower alkyl group, a lower alkoxy group, an aryl group and an aryloxy group, or a salt thereof.
 9. The optically active amine compound of formula (8) according to claim 8, wherein the lower alkyl group in X₁ to X₅ and R₂₂ means a C1-C4 alkyl group, and R₃₂ represents a phenyl or naphthyl group substituted with at least one group selected from a C1-C4 alkyl group, a C1-C4 alkoxy group, a phenyl group, a naphthyl group, a phenoxy group and a naphthoxy group.
 10. The optically active amine compound of formula (8) according to claim 8, wherein X₁ and X₃ respectively represent a halogen atom and X₂, X₄ and X₅ are hydrogen atoms.
 11. The optically active amine compound of formula (8) according to claim 10, wherein said halogen atom is a chlorine atom.
 12. The optically active amine compound of formula (8) according to claim 9, 10 or 11, wherein R₃₂ is a 3-phenoxyphenyl group or a 4-phenylphenyl group.
 13. A method for producing an optically active amine compound of formula (8) as defined in claim 8, which comprises subjecting an imine compound of formula (11):

wherein X₁ to X₅, R₂₂ and R₃₂ are the same as defined above, to a reduction reaction.
 14. An imine compound of formula (11):

wherein X₁ represents a halogen atom, or a lower alkyl group, X₂ to X₅ are the same or different and independently represent a hydrogen atom, a halogen atom, a nitro group or a lower alkyl group, R₂₂ represents a lower alkyl group, and R₃₂ represents an aryl group substituted with at least one group selected from a lower alkyl group, a lower alkoxy group, an aryl group and an aryloxy group.
 15. A method for producing an imine compound of formula (11) defined in claim 14, which comprises: reacting an optically active amine compound of formula (9):

wherein X₁ to X₅ and R₂₂ are the same as defined in connection with the imine compound of formula (11), with an aldehyde of formula (10): R₃₂—CHO   (10), wherein R₃₂ is the same as defined in connection with the imine compound of formula (11). 